Current perspectives of viral hepatitis.

Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. The five liver-specific viruses: Hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus, each have their own unique epidemiology, structural biology, transmission, endemic patterns, risk of liver complications, and response to antiviral therapies. There remain few options for treatment, in spite of the increasing prevalence of viral-hepatitis-caused liver disease. Furthermore, chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality, even though effective treatments are available that could reduce or prevent most patients' complications. In 2016, the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030, along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis. Today, treatment is sufficiently able to prevent the disease from reaching advanced phases. However, future therapies must be extremely safe, and should ideally limit the period of treatment necessary. A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis. This review aims to summarize the current state of knowledge on each type of viral hepatitis, together with major innovations.

Penile and scrotal strangulation by stainless steel rings in an human immunodeficiency virus positive man: A case report.

BACKGROUND: Penoscrotal constriction devices are either used as autoerotic stimuli or to increase sexual pleasure or performance by maintaining an erection for a longer period, and a variety of metallic and non-metallic objects are used. On the other hand, penile strangulation is a rare urologic emergency that requires prompt evaluation and intervention to prevent long-term complications. The goal of treating penile incarceration is to remove the foreign object as soon as possible. On the other hand, removal can be very challenging, and often requires resourcefulness and a multidisciplinary approach. CASE SUMMARY: A 47-year-old man who has sex with men was transferred to our hospital for persistent phallodynia and scrotal pain, accompanying swelling due to strangulation by stainless steel rings. His medical history included acquired immunodeficiency syndrome. One day prior, he had put three stainless steel rings on his penis and scrotum before sexual intercourse. After sexual intercourse, he was unable to remove them, due to swelling of his penis and scrotum. The swelling persisted, and he felt pain in the affected area the next day, then he was transferred to our hospital by ambulance. The emergency department found that his penis and scrotum were markedly engorged and swollen. We established a diagnosis of penile and scrotal strangulation by stainless steel rings. We unsuccessfully attempted to cut the rings using a cutter, then requested a rescue team via emergency medical service. They cut through each ring in two places, using an electric-powered angle grinder, and successfully removed all of the pieces. Finally, he was discharged and went home. CONCLUSION: We report the first case of penile and scrotal strangulation by stainless steel rings in an human immunodeficiency virus positive person.

Secondary pulmonary infection by Fusarium solani and Aspergillus niger during systemic steroid treatment for COVID-19: A case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-associated invasive pulmonary aspergillosis presents a diagnostic challenge due to its non-specific clinical/ imaging features, as well as the fact that the proposed clinically diagnostic algorithms do not necessarily apply to COVID-19 patients. In addition, Fusarium spp. is a rare cause of opportunistic life-threatening fungal infections. Disseminated Fusarium infection in an immunocompromised host is intractable, with a high likelihood of resulting mortality. To our knowledge, this is the first case of secondary pulmonary infection by Fusarium solani (F. solani) and Aspergillus niger (A. niger) during systemic steroid treatment for COVID-19. CASE SUMMARY: A 62-year-old male was transported to our hospital by ambulance with a complaint of fever and dyspnea. We established a diagnosis of pneumococcal pneumonia, complicated with COVID-19 and septic shock, together with acute renal failure. He was admitted to the intensive care unit, to be treated with piperacillin/tazobactam, vancomycin, and 6.6 mg per day of dexamethasone sodium phosphate, along with noradrenaline as a vasopressor, ventilator management, and continuous hemodiafiltration. His condition improved, and we finished the vasopressor on the fifth hospital day. We administered dexamethasone for ten days, and finished the course of treatment. On the eleventh day, patient respiratory deterioration was observed, and a computed tomography scan showed an exacerbation of bilateral ground-glass-opacity-like consolidation, together with newly appeared cavitary lesions in the lung. we changed antibiotics to meropenem plus vancomycin. In addition, a fungal infection was considered as a possibility based on microscopic findings of sputum, and we began coadministration of voriconazole. However, the pneumonia worsened, and the patient died on the seventeenth day of illness. Later, F. solani and A. niger were identified from sputum collected on the twelfth day. It was believed that he developed a cell-mediated immune deficiency during COVID-19 treatment, which led to the complication of pneumonia caused by the above-mentioned fungi, contributing to his death. CONCLUSION: Because early initiation of intense antifungal therapy offers the best chance for survival in pulmonary fusariosis, computed tomography scans and appropriate microbiologic investigations should be obtained for severely immunocompromised patients.

High doses of dextromethorphan induced shock and convulsions in a 19-year-old female: A case report.

BACKGROUND: Dextromethorphan is a prevalent antitussive agent that can be easily obtained as an over-the-counter medication. There has been a growing number of reported cases of toxicity in recent years. Generally, there are numerous instances of mild symptoms, with only a limited number of reports of severe cases necessitating intensive care. We presented the case of a female who ingested 111 tablets of dextromethorphan, leading to shock and convulsions and requiring intensive care that ultimately saved her life. CASE SUMMARY: A 19-year-old female was admitted to our hospital via ambulance, having overdosed on 111 tablets of dextromethorphan (15 mg) obtained through an online importer in a suicide attempt. The patient had a history of drug abuse and multiple self-inflicted injuries. At the time of admission, she exhibited symptoms of shock and altered consciousness. However, upon arrival at the hospital, the patient experienced recurrent generalized clonic convulsions and status epilepticus, necessitating tracheal intubation. The convulsions were determined to have been caused by decreased cerebral perfusion pressure secondary to shock, and noradrenaline was administered as a vasopressor. Gastric lavage and activated charcoal were also administered after intubation. Through systemic management in the intensive care unit, the patient's condition stabilized, and the need for vasopressors ceased. The patient regained consciousness and was extubated. The patient was subsequently transferred to a psychiatric facility, as suicidal ideation persisted. CONCLUSION: We report the first case of shock caused by an overdose of dextromethorphan.

Hemorrhagic shock due to submucosal esophageal hematoma along with mallory-weiss syndrome: A case report.

BACKGROUND: Esophageal submucosal hematoma is a rare condition. Although the exact etiology remains uncertain, vessel fragility with external factors is believed to have led to submucosal bleeding and hematoma formation; the vessel was ruptured by a sudden increase in pressure due to nausea, and the hematoma was enlarged by antiplatelet or anticoagulant therapy. Serious conditions are rare, with a better prognosis. We present the first known case of submucosal esophageal hematoma-subsequent hemorrhagic shock due to Mallory-Weiss syndrome. CASE SUMMARY: A 73-year-old female underwent endovascular treatment for an unruptured cerebral aneurysm. The patient received aspirin and clopidogrel before surgery and heparin during surgery, and was well during the surgery. Several hours after returning to the ICU, she complained of chest discomfort, vomited 500 mL of fresh blood, and entered hemorrhagic shock. Esophageal submucosal hematoma with Mallory-Weiss syndrome was diagnosed through an endoscopic examination and computed tomography. In addition to a massive fluid and erythrocyte transfusion, we performed a temporary compression for hemostasis with a Sengstaken-Blakemore (S-B) tube. Afterwards, she became hemodynamically stable. On postoperative day 1, we performed an upper gastrointestinal endoscopy and confirmed no expansion of the hematoma nor any recurring bleeding; therefore, we removed the S-B tube and clipped the gastric mucosal laceration at the esophagogastric junction. We started oral intake on postoperative day 10. The patient made steady progress, and was discharged on postoperative day 33. CONCLUSION: We present the first known case of submucosal esophageal hematoma subsequent hemorrhagic shock due to Mallory-Weiss syndrome.

Obligate aerobic, gram-positive, weak acid-fast, nonmotile bacilli, Tsukamurella tyrosinosolvens: Minireview of a rare opportunistic pathogen.

Tsukamurella species are obligate aerobic, gram-positive, weak acid-fast, nonmotile bacilli. They are found in various environments, such as soil, water, sludge, and petroleum reservoir wastewater, and belong to the order Actinomycetales. In 2016, there was a reclassification of species within the genus Tsukamurella, merging the species Tsukamurella tyrosinosolvens (T. tyrosinosolvens) and Tsukamurella carboxydivorans. Tsukamurella species are clinically considered to be a rare opportunistic pathogen, because most reported cases have been related to bacteremia and intravascular prosthetic devices and immunosuppression. To date, it has been isolated only from human specimens, and has always been associated with clinical disease; human infections are very rare. Reported infections have included pneumonia, brain abscesses, catheter-related bloodstream infections, ocular infections, bacteremia, and sepsis presenting with septic pulmonary emboli in patients who are immunocompromised. To date, there is no commercially available test for identification. On the other hand, sequence-based identification, including matrix-assisted laser desorption ionization time-of-flight mass spectrometry, is an alternative method for identifying clinical isolates that are either slow growers or difficult to identify through biochemical profiling. The golden standards for diagnosis and optimal management still remain to be determined. However, newer molecular biological techniques can provide accurate identification, and contribute to the appropriate selection of definitive therapy for infections caused by this organism. Combinations of several antimicrobial agents have been proposed for treatment, though the length of treatment for infections has yet to be determined, and should be individualized according to clinical response. Immunocompromised patients often experience severe cases due to infection, and life-threatening T. tyrosinosolvens events associated with dissemination and/or failure of source control have occurred. Favorable prognoses can be achieved through earlier identification of the cause of infection, as well as successful management, including appropriate antibiotic therapy together with source control. Further analyses of similar cases are required to establish the most adequate diagnostic methods and treatment regimens for infections.

ST-Elevation Acute Myocardial Infarction in a Young Man.

Acute myocardial infarction (AMI) in young patients is very rare, but the incidence has increased over years past at younger ages, likely due to the presence of multiple risk factors. We present the first known case of ST-elevation AMI (STEMI) in a young man. A 22-year-old Japanese man was transferred to our hospital due to suddenly occurred anterior chest pain. An electrocardiogram revealed ST elevation in anteroseptal leads together with reciprocal ST depression in inferior leads. An emergency coronary angiogram was performed, revealing a 100% occlusion at segment 6 of the coronary artery and we established a diagnosis of STEMI. The lesion was expanded to 0% stenosis through plain old balloon angioplasty, after which a third-generation drug-eluting stent was installed there. Afterwards, the patient was discharged on day 17. In this case, a combination of mild six risk factors plus family history of hypertension might lead to this atypical event.

Amebic liver abscess by Entamoeba histolytica.

Amebic liver abscesses (ALAs) are the most commonly encountered extraintestinal manifestation of human invasive amebiasis, which results from Entamoeba histolytica (E. histolytica) spreading extraintestinally. Amebiasis can be complicated by liver abscess in 9% of cases, and ALAs led to almost 50000 fatalities worldwide in 2010. Although there have been fewer and fewer cases in the past several years, ALAs remain an important public health problem in endemic areas. E. histolytica causes both amebic colitis and liver abscess by breaching the host's innate defenses and invading the intestinal mucosa. Trophozoites often enter the circulatory system, where they are filtered in the liver and produce abscesses, and develop into severe invasive diseases such as ALAs. The clinical presentation can appear to be colitis, including upper-right abdominal pain accompanied by a fever in ALA cases. Proper diagnosis requires nonspecific liver imaging as well as detecting anti-E. histolytica antibodies; however, these antibodies cannot be used to distinguish between a previous infection and an acute infection. Therefore, diagnostics primarily aim to use PCR or enzyme-linked immunosorbent assay to detect E. histolytica. ALAs can be treated medically, and percutaneous catheter drainage is only necessary in approximately 15% of cases. The indicated treatment is to administer an amebicidal drug (such as tinidazole or metronidazole) and paromomycin or other luminal cysticidal agent for clinical disease. Prognosis is good with almost universal recovery. Establishing which diagnostic methods are most efficacious will necessitate further analysis of similar clinical cases.

Exophiala dermatitidis.

Exophiala is a genus comprising several species of opportunistic black yeasts, which belongs to Ascomycotina. It is a rare cause of fungal infections. However, infections are often chronic and recalcitrant, and while the number of cases is steadily increasing in both immunocompromised and immunocompetent people, detailed knowledge remains scarce regarding infection mechanisms, virulence factors, specific predisposing factors, risk factors, and host response. The most common manifestations of Exophiala infection are skin infections, and the most frequent type of deep infection is pulmonary infection due to inhalation. The invasive disease ranges from cutaneous or subcutaneous infection to systemic dissemination to internal organs. The final identification of the causative organism should be achieved through a combination of several methods, including the newly introduced diagnostic analysis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, together with sequencing of the ribosomal ribonucleic acid internal transcribed spacer region of the fungi, and histological and culture findings. Regarding treatment, because anti-infective agents and natural compounds exhibited poor antibiofilm activity, few treatments have ultimately been found to be effective for specific antifungal therapy, so the optimal antifungal therapy and duration of therapy for these infections remain unknown. Therefore, most forms of disease caused by Exophiala dermatitidis require aggressive combination therapies: Both surgical intervention and aggressive antifungal therapy with novel compounds and azoles are necessary for effective treatment.

Angiotensin receptor blocker neprilysin inhibitors.

Heart failure (HF) is a clinical syndrome that results from a structural or functional cardiac disorder that reduces the ability of the ventricle of the heart to fill with, or eject, blood. It is a multifaceted clinical condition that affects up to 2% of the population in the developed world, and is linked to significant morbidity and mortality; it is therefore considered a major concern for public health. Regarding the mechanism of HF, three neurohumoral factors - the renin-angiotensin-aldosterone system, the sympathetic nervous system, and natriuretic peptides - are related to the pathology of chronic HF (CHF), and the targets of treatment. Angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor), namely sacubitril/valsartan (SAC/VAL), has been introduced as a treatment for CHF. SAC/VAL is an efficacious, safe, and cost-effective therapy that improves quality of life and longevity in patients with HF with reduced ejection fraction (HFrEF), and reduces hospital admissions. An in-hospital initiation strategy offers a potential new avenue to improve the clinical uptake of SAC/VAL. In the last five years, SAC/VAL has been established as a cornerstone component of comprehensive disease-modifying medical therapy in the management of chronic HFrEF. On the other hand, further work, with carefully designed and controlled preclinical studies, is necessary for understanding the molecular mechanisms, effects, and confirmation of issues such as long-term safety in both human and animal models.

Diffuse large B cell lymphoma originating from the maxillary sinus with skin metastases: A case report and review of literature.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma (ML), accounting for 30%-40% of cases of non-Hodgkin's lymphoma (NHL) in adults. Primary paranasal sinus lymphoma is a rare presentation of extranodal NHL that accounts for only 0.17% of all lymphomas. ML from the maxillary sinus (MS) is a particularly rare presentation, and is thus often difficult to diagnose. We have reported the first known case of DLBCL originating from the MS with rapidly occurrent multiple skin metastasis. CASE SUMMARY: An 81-year-old Japanese man visited our hospital due to continuous pain for 12 d in the left maxillary nerve area. His medical history included splenectomy due to a traffic injury, an old right cerebral infarction from when he was 74-years-old, hypertension, and type 2 diabetes mellitus. A plain head computed tomography (CT) scan revealed a 3 cm × 3.1 cm × 3 cm sized left MS. On day 25, left diplopia and ptosis occurred, and a follow-up CT on day 31 revealed the growth of the left MS mass. Based on an MS biopsy on day 50, we established a definitive diagnosis of DLBCL, non-germinal center B-cell-like originating from the left MS. The patient was admitted on day 62 due to rapid deterioration of his condition, and a plain CT scan revealed the further growth of the left MS mass, as well as multiple systemic metastasis, including of the skin. A skin biopsy on day 70 was found to be the same as that of the left MS mass. We notified the patient and his family of the disease, and they opted for palliative care, considering on his condition and age. The patient died on day 80. CONCLUSION: This case suggests the need for careful, detailed examination, and for careful follow-up, when encountering patients presenting with a mass.

A SNARE geranylgeranyltransferase essential for the organization of the Golgi apparatus.

Protein prenylation is essential for many cellular processes including signal transduction, cytoskeletal reorganization, and membrane trafficking. Here, we identify a novel type of protein prenyltransferase, which we named geranylgeranyltransferase type-III (GGTase-III). GGTase-III consists of prenyltransferase alpha subunit repeat containing 1 (PTAR1) and the ß subunit of RabGGTase. Using a biotinylated geranylgeranyl analogue, we identified the Golgi SNARE protein Ykt6 as a substrate of GGTase-III. GGTase-III transfers a geranylgeranyl group to mono-farnesylated Ykt6, generating doubly prenylated Ykt6. The crystal structure of GGTase-III in complex with Ykt6 provides structural basis for Ykt6 double prenylation. In GGTase-III-deficient cells, Ykt6 remained in a singly prenylated form, and the Golgi SNARE complex assembly was severely impaired. Consequently, the Golgi apparatus was structurally disorganized, and intra-Golgi protein trafficking was delayed. Our findings reveal a fourth type of protein prenyltransferase that generates geranylgeranyl-farnesyl Ykt6. Double prenylation of Ykt6 is essential for the structural and functional organization of the Golgi apparatus.

Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α.

Synapse formation is induced by transsynaptic interaction of neuronal cell-adhesion molecules termed synaptic organizers. Type IIa receptor protein tyrosine phosphatases (IIa RPTPs) function as presynaptic organizers. The cytoplasmic domain of IIa RPTPs consists of two phosphatase domains, and the membrane-distal one (D2) is essential for synapse formation. Liprin-α, which is an active zone protein critical for synapse formation, interacts with D2 via its C-terminal domain composed of three tandem sterile alpha motifs (tSAM). Structural mechanisms of this critical interaction for synapse formation remain elusive. Here, we report the crystal structure of the complex between mouse PTPδ D2 and Liprin-α3 tSAM at 1.91 Å resolution. PTPδ D2 interacts with the N-terminal helix and the first and second SAMs (SAM1 and SAM2, respectively) of Liprin-α3. Structure-based mutational analyses in vitro and in cellulo demonstrate that the interactions with Liprin-α SAM1 and SAM2 are essential for the binding and synaptogenic activity.

Structural basis of guanine nucleotide exchange for Rab11 by SH3BP5.

The Rab GTPase family is a major regulator of membrane traffic in eukaryotic cells. The Rab11 subfamily plays important roles in specific trafficking events such as exocytosis, endosomal recycling, and cytokinesis. SH3BP5 and SH3BP5-like (SH3BP5L) proteins have recently been found to serve as guanine nucleotide exchange factors (GEF) for Rab11. Here, we report the crystal structures of the SH3BP5 GEF domain alone and its complex with Rab11a. SH3BP5 exhibits a V-shaped structure comprising two coiled coils. The coiled coil composed of α1, and α4 is solely responsible for the Rab11a binding and GEF activity. SH3BP5 pulls out and deforms switch I of Rab11a so as to facilitate the GDP release from Rab11a. SH3BP5 interacts with the N-terminal region, switch I, interswitch, and switch II of Rab11a. SH3BP5 and SH3BP5L localize to Rab11-positive recycling endosomes and show GEF activity for all of the Rab11 family but not for Rab14. Fluorescence-based GEF assays combined with site-directed mutagenesis reveal the essential interactions between SH3BP5 and Rab11 family proteins for the GEF reaction on recycling endosomes.

Structural basis of ubiquitin recognition by the winged-helix domain of Cockayne syndrome group B protein.

Cockayne syndrome group B (CSB, also known as ERCC6) protein is involved in many DNA repair processes and essential for transcription-coupled repair (TCR). The central region of CSB has the helicase motif, whereas the C-terminal region contains important regulatory elements for repair of UV- and oxidative stress-induced damages and double-strand breaks (DSBs). A previous study suggested that a small part (∼30 residues) within this region was responsible for binding to ubiquitin (Ub). Here, we show that the Ub-binding of CSB requires a larger part of CSB, which was previously identified as a winged-helix domain (WHD) and is involved in the recruitment of CSB to DSBs. We also present the crystal structure of CSB WHD in complex with Ub. CSB WHD folds as a single globular domain, defining a class of Ub-binding domains (UBDs) different from 23 UBD classes identified so far. The second α-helix and C-terminal extremity of CSB WHD interact with Ub. Together with structure-guided mutational analysis, we identified the residues critical for the binding to Ub. CSB mutants defective in the Ub binding reduced repair of UV-induced damage. This study supports the notion that DSB repair and TCR may be associated with the Ub-binding of CSB.

Structural insights into modulation and selectivity of transsynaptic neurexin-LRRTM interaction.

Leucine-rich repeat transmembrane neuronal proteins (LRRTMs) function as postsynaptic organizers that induce excitatory synapses. Neurexins (Nrxns) and heparan sulfate proteoglycans have been identified as presynaptic ligands for LRRTMs. Specifically, LRRTM1 and LRRTM2 bind to the Nrxn splice variant lacking an insert at the splice site 4 (S4). Here, we report the crystal structure of the Nrxn1ß-LRRTM2 complex at 3.4 Å resolution. The Nrxn1ß-LRRTM2 interface involves Ca2+-mediated interactions and overlaps with the Nrxn-neuroligin interface. Together with structure-based mutational analyses at the molecular and cellular levels, the present structural analysis unveils the mechanism of selective binding between Nrxn and LRRTM1/2 and its modulation by the S4 insertion of Nrxn.

Structural insights into ubiquitin phosphorylation by PINK1.

Mutations of PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin (Ub) ligase parkin can cause familial parkinsonism. These two proteins are essential for ubiquitylation of damaged mitochondria and subsequent degradation. PINK1 phosphorylates Ser65 of Ub and the Ub-like (UBL) domain of parkin to allosterically relieve the autoinhibition of parkin. To understand the structural mechanism of the Ub/UBL-specific phosphorylation by PINK1, we determined the crystal structure of Tribolium castaneum PINK1 kinase domain (TcPINK1) in complex with a nonhydrolyzable ATP analogue at 2.5 Å resolution. TcPINK1 consists of the N- and C-terminal lobes with the PINK1-specific extension. The ATP analogue is bound in the cleft between the N- and C-terminal lobes. The adenine ring of the ATP analogue is bound to a hydrophobic pocket, whereas the triphosphate group of the ATP analogue and two coordinated Mg ions interact with the catalytic hydrophilic residues. Comparison with protein kinases A and C (PKA and PKC, respectively) unveils a putative Ub/UBL-binding groove, which is wider than the peptide-binding groove of PKA or PKC to accommodate the globular head of Ub or UBL. Further crosslinking analyses suggested a PINK1-interacting surface of Ub. Structure-guided mutational analyses support the findings from the present structural analysis of PINK1.

Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22.

Epilepsy is a common brain disorder throughout history. Epilepsy-related ligand-receptor complex, LGI1-ADAM22, regulates synaptic transmission and has emerged as a determinant of brain excitability, as their mutations and acquired LGI1 autoantibodies cause epileptic disorders in human. Here, we report the crystal structure of human LGI1-ADAM22 complex, revealing a 2:2 heterotetrameric assembly. The hydrophobic pocket of the C-terminal epitempin-repeat (EPTP) domain of LGI1 binds to the metalloprotease-like domain of ADAM22. The N-terminal leucine-rich repeat and EPTP domains of LGI1 mediate the intermolecular LGI1-LGI1 interaction. A pathogenic R474Q mutation of LGI1, which does not exceptionally affect either the secretion or the ADAM22 binding, is located in the LGI1-LGI1 interface and disrupts the higher-order assembly of the LGI1-ADAM22 complex in vitro and in a mouse model for familial epilepsy. These studies support the notion that the LGI1-ADAM22 complex functions as the trans-synaptic machinery for precise synaptic transmission.

Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168.

The E3 ubiquitin (Ub) ligase RNF168 plays a critical role in the initiation of the DNA damage response to double-strand breaks (DSBs). The recruitment of RNF168 by ubiquitylated targets involves two distinct regions, Ub-dependent DSB recruitment module (UDM) 1 and UDM2. Here we report the crystal structures of the complex between UDM1 and Lys63-linked diUb (K63-Ub2) and that between the C-terminally truncated UDM2 (UDM2ΔC) and K63-Ub2. In both structures, UDM1 and UDM2ΔC fold as a single α-helix. Their simultaneous bindings to the distal and proximal Ub moieties provide specificity for Lys63-linked Ub chains. Structural and biochemical analyses of UDM1 elucidate an Ub-binding mechanism between UDM1 and polyubiquitylated targets. Mutations of Ub-interacting residues in UDM2 prevent the accumulation of RNF168 to DSB sites in U2OS cells, whereas those in UDM1 have little effect, suggesting that the interaction of UDM2 with ubiquitylated and polyubiquitylated targets mainly contributes to the RNF168 recruitment.

Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation.

Synapse formation is triggered by trans-synaptic interactions of cell adhesion molecules, termed synaptic organizers. Three members of type-II receptor protein tyrosine phosphatases (classified as type-IIa RPTPs; PTPδ, PTPσ and LAR) are known as presynaptic organizers. Synaptic adhesion-like molecules (SALMs) have recently emerged as a family of postsynaptic organizers. Although all five SALM isoforms can bind to the type-IIa RPTPs, only SALM3 and SALM5 reportedly have synaptogenic activities depending on their binding. Here, we report the crystal structures of apo-SALM5, and PTPδ-SALM2 and PTPδ-SALM5 complexes. The leucine-rich repeat (LRR) domains of SALMs interact with the second immunoglobulin-like (Ig) domain of PTPδ, whereas the Ig domains of SALMs interact with both the second and third Ig domains of PTPδ. Unexpectedly, the structures exhibit the LRR-mediated 2:2 complex. Our synaptogenic co-culture assay using site-directed SALM5 mutants demonstrates that presynaptic differentiation induced by PTPδ-SALM5 requires the dimeric property of SALM5.