NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues.

NF2-related schwannomatosis (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2 deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2 deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Cyclin-dependent kinase 1 depolymerizes nuclear lamin filaments by disrupting the head-to-tail interaction of the lamin central rod domain.

Nuclear lamins maintain the nuclear envelope structure by forming long linear filaments via two alternating molecular arrangements of coiled-coil dimers, known as A11 and A22 binding modes. The A11 binding mode is characterized by the antiparallel interactions between coil 1b domains, whereas the A22 binding mode is facilitated by interactions between the coil 2 domains of lamin. The junction between A11- and A22-interacting dimers in the lamin tetramer produces another parallel head-tail interaction between coil 1a and the C-terminal region of coil 2, called the ACN interaction. During mitosis, phosphorylation in the lamin N-terminal head region by the cyclin-dependent kinase (CDK) complex triggers depolymerization of lamin filaments, but the associated mechanisms remain unknown at the molecular level. In this study, we revealed using the purified proteins that phosphorylation by the CDK1 complex promotes disassembly of lamin filaments by directly abolishing the ACN interaction between coil 1a and the C-terminal portion of coil 2. We further observed that this interaction was disrupted as a result of alteration of the ionic interactions between coil 1a and coil 2. Combined with molecular modeling, we propose a mechanism for CDK1-dependent disassembly of the lamin filaments. Our results will help to elucidate the cell cycle-dependent regulation of nuclear morphology at the molecular level.

A Combination of Bio-Orthogonal Supramolecular Clicking and Proximity Chemical Tagging as a Supramolecular Tool for Discovery of Putative Proteins Associated with Laminopathic Disease.

Protein mutations alter protein-protein interactions that can lead to a number of illnesses. Mutations in lamin A (LMNA) have been reported to cause laminopathies. However, the proteins associated with the LMNA mutation have mostly remained unexplored. Herein, a new chemical tool for proximal proteomics is reported, developed by a combination of proximity chemical tagging and a bio-orthogonal supramolecular latching based on cucurbit[7]uril (CB[7])-based host-guest interactions. As this host-guest interaction acts as a noncovalent clickable motif that can be unclicked on-demand, this new chemical tool is exploited for reliable detection of the proximal proteins of LMNA and its mutant that causes laminopathic dilated cardiomyopathy (DCM). Most importantly, a comparison study reveals, for the first time, mutant-dependent alteration in LMNA proteomic environments, which allows to identify putative laminopathic DCM-linked proteins including FOXJ3 and CELF2. This study demonstrates the feasibility of this chemical tool for reliable proximal proteomics, and its immense potential as a new research platform for discovering biomarkers associated with protein mutation-linked diseases.

Structural basis for the interaction between unfarnesylated progerin and the Ig-like domain of lamin A/C in premature aging disorders.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by C-terminally truncated lamin A, termed as the pre-progerin product. Progerin is a C-terminally farnesylated protein derived from pre-progerin, which causes nuclear deformation at the inner-nuclear membrane. As an alternative or additional mechanism, a farnesylation-independent abnormal interaction between the C-terminus of progerin and Ig-like domain has been proposed. However, the molecular mechanism underlying the role of unfarnesylated C-terminus of pre-progerin in HGPS remains largely unknown. In this study, we determined the crystal structures of C-terminal peptide of progerin and Ig-like domain of lamin A/C. Results showed that the C-terminal cysteine residue of progerin forms a disulfide bond with the only cysteine residue of the Ig-like domain. This finding suggested that unfarnesylated progerin can form a disulfide bond with the Ig-like domain in the lamin meshwork. The Alphafold2-assisted docking structure showed that disulfide bond formation was promoted by a weak interaction between the groove of Ig-like domain and the unfarnesylated C-terminal tail region of progerin. Our results provide molecular insights into the normal aging process as well as premature aging of humans.

Beta-strand-mediated dimeric formation of the Ig-like domains of human lamin A/C and B1.

Lamins are nuclear intermediate filament proteins that play an essential role in maintaining the nuclear structure by forming a 3-D meshwork. Lamins consist of the N-terminal unstructured head, the coiled-coil rod domain, and the C-terminal tail, which is mostly unstructured except for the Ig-like domain. To date, the Ig-like domain has been characterized as a monomeric structure. Here, we determined the crystal structures of human lamin A/C, including the Ig-like domain and its N- and C-terminal flanking sequences. Interestingly, the structures showed a homodimer formed by beta-strand interactions between the N- and C-terminal flanking sequences. This interaction also provides a molecular implication for the creation of a 3-D meshwork between the 3.5-nm-thick filaments. Furthermore, we determined the crystal structure of the corresponding region of lamin B1. The structure showed a similar dimeric assembly, also formed by beta-strand interactions, albeit the intersubunit distance was much shorter. Since the Ig-like domain contains many genetic hotspots causing lamin-related diseases in lamin A/C, our findings will help understand the detailed assembly of lamins in a 3-D meshwork structure and lamin-related diseases at the molecular level.

Effect of Helicobacter pylori infection and its eradication on gastric regenerating atypia in 22 133 subjects.

BACKGROUND AND AIM: The aim of this study was to identify factors affecting persistent gastric regenerating atypia and determine the effect of Helicobacter pylori eradication on the course of this lesion. METHODS: In cross-sectional setting, comprehensive health check-up subjects who underwent both endoscopy and H. pylori test from 2001 to 2009 were included. The association between H. pylori and gastric regenerating atypia was evaluated. In cohort setting, patients with regenerating atypia who underwent H. pylori test from 2001 to 2013 were included. Factors affecting positive pathology (persistent regenerating atypia or new development of neoplasm) in patients with regenerating atypia at baseline were investigated. RESULTS: In cross-sectional setting, regenerating atypia was observed in 1.1% (241/22 133). H. pylori infection was associated with gastric regenerating atypia (adjusted odds ratio, 1.47; 95% confidence interval [CI], 1.12-1.91). In cohort setting, 310 patients with regenerating atypia were finally eligible. Positive pathology rate during follow up was 16.1% (15/93) in the persistent infection group, 2.8% (3/106) in successful eradication group, and 4.5% (5/111) in baseline H. pylori-negative group. Persistent H. pylori infection increased the risk of positive pathology (adjusted risk ratio [RR], 7.18; 95% CI, 1.95-26.48) compared to H. pylori eradication group. Persistent H. pylori infection increased the risk of regenerative atypia (adjusted RR, 5.70; 95% CI, 1.46-22.17) and new neoplasm (adjusted RR, 10.74; 95% CI, 1.10-105.17) compared to baseline negative H. pylori. CONCLUSIONS: H. pylori infection is an independent risk factor for gastric regenerating atypia. Eradication of H. pylori seems helpful for regression of regenerating atypia.

Effect of Helicobacter pylori eradication and high-density lipoprotein on the risk of de novo gastric cancer development.

BACKGROUND AND AIMS: The effect of Helicobacter pylori eradication on de novo gastric cancer is controversial, although meta-analyses suggest a reduction in gastric cancer after eradication. The effect of high-density lipoprotein (HDL) on gastric cancer has been rarely reported. METHODS: In this large retrospective cohort study, participants underwent endoscopy and H pylori testing from 2003 to 2011 and underwent follow-up endoscopy and H pylori testing until 2013. H pylori infection was detected using a rapid urease test or histologic test. The H pylori eradication group was defined as successful eradication, whereas the H pylori persistent group was defined as noneradication or eradication failure. The risk of cancer was measured with hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 10,328 healthy subjects (5951 men; mean age, 48.7 years), 31 gastric cancers were detected during a median follow-up of 5.5 years. De novo gastric cancer developed in 21 of 3508 subjects (.6%) in the noneradication group, 4 of 2050 subjects (.2%) in the successful eradication group, and 6 of 4770 participants (.13%) in the absence of H pylori group. In the adjusted analysis, H pylori eradication decreased de novo gastric cancer risk (HR, .29; 95% CI, .10-.86) compared with the persistent group. The risk of de novo gastric cancer in absence of H pylori was also much lower compared with the persistent group (HR, .24; 95% CI, .09-.60). Low serum HDL increased the risk of de novo gastric cancer (HR, 2.67; 95% CI, 1.14-6.16). CONCLUSIONS: Successful H pylori eradication reduced de novo gastric cancer, whereas low HDL increased its risk.

Helicobacter pylori infection is an independent risk factor for colonic adenomatous neoplasms.

PURPOSE: Helicobacter pylori infection is considered to have a positive association with colorectal neoplasms. In this study, we evaluated the association between H. pylori infection and colorectal adenomas, based on the characteristics of these adenomas in Korea, where the prevalence of H. pylori infection is high and the incidence of colorectal cancer continues to increase. METHODS: The study cohort consisted of 4,466 subjects who underwent colonoscopy and esophagogastroduodenoscopy during screening (1,245 colorectal adenomas vs. 3,221 polyp-free controls). We compared the rate of H. pylori infection between patients with adenoma and polyp-free control cases, using multivariable logistic regression analysis. RESULTS: The overall rate of positive H. pylori infection was higher in adenoma cases than in polyp-free control cases (55.0 vs. 48.5%, p < 0.001). The odds ratio (OR) of positive H. pylori infection in patients with adenoma compared to polyp-free controls was 1.28 (95% CI 1.11-1.47). The positive association of H. pylori infection with colorectal adenomas was more prominent in advanced adenomas (OR 1.84, 95% CI 1.25-2.70) and multiple adenomas (OR 1.72, 95% CI 1.26-2.35). Based on the location of these adenomas, the OR was significant only in patients with colonic adenomas (OR 1.31, 95% CI 1.13-1.52) and not in those with rectal adenoma (OR 0.85, 95% CI 0.58-1.24). CONCLUSION: Helicobacter pylori infection is an independent risk factor for colonic adenomas, especially in cases of advanced or multiple adenomas, but not for rectal adenomas.

Visceral Adipose Tissue Volume and the Occurrence of Colorectal Adenoma in Follow-up Colonoscopy for Screening and Surveillance.

Whether obesity accelerates adenoma recurrence is not yet clear; therefore, we analyzed the risk factors for adenoma occurrence at follow-up colonoscopy, with a focus on visceral adiposity. In total, 1516 subjects underwent index colonoscopy, computed tomography, and questionnaire assessment from February to May 2008; 539 subjects underwent follow-up colonoscopy at the National Cancer Center at least 6 mo after the index colonoscopy. The relationships between the presence of adenoma at follow-up colonoscopy and anthropometric obesity measurements, including body mass index (BMI), waist circumference (WC), visceral adipose tissue (VAT) volume, and subcutaneous adipose tissue (SAT) volume, were analyzed. 188 (34.9%) had adenomatous polyps at follow-up colonoscopy. Multivariate analysis revealed that VAT volume ≥ 1000 cm3 and BMI ≥ 30 kg/m2 were related to the presence of adenoma at follow-up colonoscopy (VAT volume 1000-1500 cm3: odds ratio [OR] = 2.13(95% confidence interval, CI = 1.06-4.26), P = 0.034; VAT volume ≥ 1000 cm3: OR = 2.24(95% CI = 1.03-4.88), P = 0.043; BMI ≥ 30 kg/m2: OR = 4.22(95% CI = 1.12-15.93), P = 0.034). In contrast, BMI 25-29.9 kg/m2, SAT volume, and WC were not associated with the presence of adenoma at follow-up colonoscopy. In conclusion, excess VAT can contribute to the development and growth of new colorectal adenomas, and is a better predictor of colorectal adenoma occurrence at follow-up colonoscopy than BMI, WC, and SAT volume.

Effects of Helicobacter pylori infection and its eradication on lipid profiles and cardiovascular diseases.

BACKGROUND: We aimed to examine the relationship of current Helicobacter pylori infection with lipid profile and cardiovascular disease and its eradication effect. METHODS: Healthy subjects, who underwent routine checkup between October 2003 and December 2007, were followed up until June 2009. Helicobacter pylori and lipid profiles were measured both baseline and follow-up. Multiple logistic regression models for odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the effects of H. pylori infection and its eradication, on lipids and cardiovascular disease. RESULTS: Current infection with H. pylori with 50.5% (6759/13383) at baseline increased low-density lipoprotein (LDL) and decreased high-density lipoprotein (HDL) than H. pylori-negative group. Successful eradication of H. pylori decreased the risk of high LDL compared with the persistent infection (OR 0.76, 95% CI 0.59-96), which was comparable to that of the persistent negative group (OR 0.82, 95% CI 0.70-0.97), and decreased the risk of low HDL (OR 0.68, 95% CI 0.49-0.96). Current infection of H. pylori increased the risk of cardiovascular disease (OR 3.27, 95% CI 1.31-8.14) at baseline, but its eradication failed to decrease the risk at a 2-year follow-up. However, persistent negative infection decreased the risk (OR 0.57, 95% CI 0.35-0.94) comparing to persistent positive infection at follow-up. CONCLUSIONS: Current infection with H. pylori had a positive association with high LDL, low HDL, and cardiovascular disease. Successful H. pylori eradication decreased the risk of high LDL and low HDL, but did not reduce the risk of cardiovascular disease.

Chemical suppression of an oncogenic splicing variant of AIMP2 induces tumour regression.

AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein 2) is a potent tumour suppressor that induces apoptosis in response to various oncogenic signals. AIMP2-DX2, an exon2-deleted splicing variant of AIMP2, is up-regulated in lung cancer and competitively suppresses the pro-apoptotic activity of AIMP2, resulting in tumorigenesis. In the present study we report that BC-DXI01, a synthetic compound, specifically reduces the cellular levels of AIMP2-DX2 through selective degradation of the AIMP2-DX2 mRNA transcript. We found that BC-DXI01-mediated cell death positively correlates with AIMP2-DX2 expression in the lung cancer cell lines tested. Administration of BC-DXI01 in a AIMP2-DX2-driven tumour xenograft mice model led to reduced tumour sizes and volumes of up to 60% in comparison with vehicle-treated mice group, consistent with decreases in AIMP2-DX2 transcript and protein levels. Taken together, our findings suggest that tumorigenic activity of AIMP2-DX2 can be controlled by the small chemical BC-DXI01, which can selectively suppress the AIMP2-DX2 mRNA transcript.

Cancer-associated splicing variant of tumor suppressor AIMP2/p38: pathological implication in tumorigenesis.

Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.

Elevated TRAF2/6 expression in Parkinson's disease is caused by the loss of Parkin E3 ligase activity.

Parkinson's disease (PD) is the second leading neurodegenerative disease, and is known to be induced by environmental factors or genetic mutations. Among the verified genetic mutations of PD, Parkin, isolated from the PARK2 locus, shows an autosomal recessive inheritance pattern and is known to be an E3 ligase. However, the physiological target of Parkin and the molecular mechanism of Parkin-deficiency-induced PD have not been clearly demonstrated until now. It has recently been proposed that inflammation, suggesting as a causal factor for PD, is enhanced by Parkin deficiency. Thus, we examined the relationship between inflammation-related factors and Parkin. Here, we provide the evidence that Parkin suppresses inflammation and cytokine-induced cell death by promoting the proteasomal degradation of TRAF2/6 (TNF-α receptor-associated factor 2/6). Overexpression of Parkin can reduce the half-lives of TRAF2 and TRAF6, whereas si-Parkin can extend them. However, mutant Parkins did not alter the expression of TRAF2/6. Thus, loss of Parkin enhances sensitivity to TNF-α- or IL-1ß-induced JNK activation and NF-κB activation. Indeed, si-Parkin-induced apoptosis is suppressed by the knockdown of TRAF6 or TRAF2. We also observed elevated expression levels of TRAF6 and a reduction of IκB in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mouse model. Moreover, elevated expression levels or aggregation of TRAF6 were detected in approximately half of the human PD tissues (7/15 cases) and 2 cases, respectively. In addition, TRAF6 and Parkin expression levels show a reverse relationship in human PD tissues. Our results strongly suggest that the reduction of Parkin or overexpression of TRAF2/6 by chronic inflammation would be the reason for occurrence of PD.

Redox-switch modulation of human SSADH by dynamic catalytic loop.

Succinic semialdehyde dehydrogenase (SSADH) is involved in the final degradation step of the inhibitory neurotransmitter gamma-aminobutyric acid by converting succinic semialdehyde to succinic acid in the mitochondrial matrix. SSADH deficiency, a rare autosomal recessive disease, exhibits variable clinical phenotypes, including psychomotor retardation, language delay, behaviour disturbance and convulsions. Here, we present crystal structures of both the oxidized and reduced forms of human SSADH. Interestingly, the structures show that the catalytic loop of the enzyme undergoes large structural changes depending on the redox status of the environment, which is mediated by a reversible disulphide bond formation between a catalytic Cys340 and an adjacent Cys342 residues located on the loop. Subsequent in vivo and in vitro studies reveal that the 'dynamic catalytic loop' confers a response to reactive oxygen species and changes in redox status, indicating that the redox-switch modulation could be a physiological control mechanism of human SSADH. Structural basis for the substrate specificity of the enzyme and the impact of known missense point mutations associated with the disease pathogenesis are presented as well.

Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation.

p38 is associated with a macromolecular tRNA synthetase complex. It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality. Here we investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38-deficient mice showed defects in lung differentiation and respiratory distress syndrome. p38 was found to interact with FUSE-binding protein (FBP), a transcriptional activator of c-myc. Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of c-myc, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (TGF-beta) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and c-myc. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of c-myc during lung differentiation.

Progerin, an Aberrant Spliced Form of Lamin A, Is a Potential Therapeutic Target for HGPS.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder caused by the mutant protein progerin, which is expressed by the abnormal splicing of the LMNA gene. HGPS affects systemic levels, with the exception of cognition or brain development, in children, showing that cellular aging can occur in the short term. Studying progeria could be useful in unraveling the causes of human aging (as well as fatal age-related disorders). Elucidating the clear cause of HGPS or the development of a therapeutic medicine could improve the quality of life and extend the survival of patients. This review aimed to (i) briefly describe how progerin was discovered as the causative agent of HGPS, (ii) elucidate the puzzling observation of the absence of primary neurological disease in HGPS, (iii) present several studies showing the deleterious effects of progerin and the beneficial effects of its inhibition, and (iv) summarize research to develop a therapy for HGPS and introduce clinical trials for its treatment.

Progerinin, an Inhibitor of Progerin, Alleviates Cardiac Abnormalities in a Model Mouse of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare human premature aging disorder that precipitates death because of cardiac disease. Almost all cases of HGPS are caused by aberrant splicing of the LMNA gene that results in the production of a mutant Lamin A protein termed progerin. In our previous study, treatment with Progerinin has been shown to reduce progerin expression and improve aging phenotypes in vitro and in vivo HGPS models. In this record, cardiac parameters (stroke volume (SV), ejection fraction (EF), fractional shortening (FS), etc.) were acquired in LmnaWT/WT and LmnaG609G/WT mice fed with either a vehicle diet or a Progerinin diet by echocardiography (from 38 weeks to 50 weeks at various ages), and then the cardiac function was analyzed. We also acquired the tissue samples and blood serum of LmnaWT/WT and LmnaG609G/WT mice for pathological analysis at the end of echocardiography. From these data, we suggest that the administration of Progerinin in the HGPS model mouse can restore cardiac function and correct arterial abnormalities. These observations provide encouraging evidence for the efficacy of Progerinin for cardiac dysfunction in HGPS.

Association of colorectal adenoma with components of metabolic syndrome.

PURPOSE: Recently, some studies have shown that diabetes mellitus and metabolic syndrome increase the risk of colorectal neoplasms. Although the mechanism is not known, those have been proposed to contribute to this phenomenon, including insulin resistance, oxidative stress, and adipokine production. The objective of this study was to assess the association between metabolic risk factors and colorectal neoplasm. METHODS: Study participants visited the National Cancer Center, Korea, for screening (2007-2009). A total of 1,771 diagnosed adenoma patients and 4,667 polyp-free controls were included. The association between risk factors and colorectal neoplasm was evaluated using logistic regression models. RESULTS: High waist circumference, blood pressure, and serum triglyceride levels were associated with an increased risk of colorectal adenoma. Metabolic syndrome (MS) was associated with an increased risk of adenoma (OR = 1.44, 95 % CI = 1.23-1.70). The association between MS and colorectal adenoma was observed regardless of advanced/low-risk adenoma, and multiplicity. MS affected right colon adenomas (OR = 1.50, 95 % CI = 1.22-1.85), left colon adenomas (OR = 1.36, 95 % CI = 1.05-1.76), and adenomas in multiple anatomical locations (OR = 1.59, 95 % CI = 1.19-2.12), but was not associated with rectum. CONCLUSION: Central obesity, triglyceride level, and MS are risk factors for colorectal adenoma including advanced adenoma and multiplicity.

Splicing Variants, Protein-Protein Interactions, and Drug Targeting in Hutchinson-Gilford Progeria Syndrome and Small Cell Lung Cancer.

Alternative splicing (AS) is a biological operation that enables a messenger RNA to encode protein variants (isoforms) that give one gene several functions or properties. This process provides one of the major sources of use for understanding the proteomic diversity of multicellular organisms. In combination with post-translational modifications, it contributes to generating a variety of protein-protein interactions (PPIs) that are essential to cellular homeostasis or proteostasis. However, cells exposed to many kinds of stresses (aging, genetic changes, carcinogens, etc.) sometimes derive cancer or disease onset from aberrant PPIs caused by DNA mutations. In this review, we summarize how splicing variants may form a neomorphic protein complex and cause diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and small cell lung cancer (SCLC), and we discuss how protein-protein interfaces obtained from the variants may represent efficient therapeutic target sites to treat HGPS and SCLC.

Crystal structure of progeria mutant S143F lamin A/C reveals increased hydrophobicity driving nuclear deformation.

Lamins are intermediate filaments that form a 3-D meshwork in the periphery of the nuclear envelope. The recent crystal structure of a long fragment of human lamin A/C visualized the tetrameric assembly unit of the central rod domain as a polymerization intermediate. A genetic mutation of S143F caused a phenotype characterized by both progeria and muscular dystrophy. In this study, we determined the crystal structure of the lamin A/C fragment harboring the S143F mutation. The obtained structure revealed the X-shaped interaction between the tetrameric units in the crystals, potentiated by the hydrophobic interactions of the mutated Phe143 residues. Subsequent studies indicated that the X-shaped interaction between the filaments plays a crucial role in disrupting the normal lamin meshwork. Our findings suggest the assembly mechanism of the 3-D meshwork and further provide a molecular framework for understanding the aging process by nuclear deformation.