Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review.

Ehlers-Danlos syndromes (EDSs) constitute a heterogeneous group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Asymptomatic EDSs, joint hypermobility without associated syndromes, EDSs, and hypermobility spectrum disorders are the commonest phenotypes associated with joint hypermobility. Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by extreme flexibility of the joints, along with pain and other symptoms. JHS can be a sign of a more serious underlying genetic condition, such as EDS, which affects the cartilage, bone, fat, and blood. The exact cause of JHS could be related to genetic changes in the proteins that add flexibility and strength to the joints, ligaments, and tendons, such as collagen. Membrane proteins are a class of proteins embedded in the cell membrane and play a crucial role in cell signaling, transport, and adhesion. Dysregulated membrane proteins have been implicated in a variety of diseases, including cancer, cardiovascular disease, and neurological disorders; recent studies have suggested that membrane proteins may also play a role in the pathogenesis of JHS. This article presents an exploration of the causative factors contributing to musculoskeletal pain in individuals with hypermobility, based on research findings. It aims to provide an understanding of JHS and its association with membrane proteins, addressing the clinical manifestations, pathogenesis, diagnosis, and management of JHS.

Identification of potential inhibitors of SARS-CoV-2 S protein-ACE2 interaction by in silico drug repurposing.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus discovered that appeared in Wuhan, China, in December 2019, causes COVID-19 disease which have resulted in cases similar to SARS-atypical pneumonia. As of March 1, 2021, Mexico had reached 2.11 million cases of COVID-19 and 189 thousand deaths; around 116 million cases and 2.57 million deaths are reported worldwide with new cases and increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represents an alternative strategy to block the binding of SARS-CoV-2 protein S and forestall virus adhesion, internalization and replication in the host cell. Methods: Rigid molecular docking was performed using receptor binding domain of the S1 subunit of S protein (RBD S1)-ACE2 (PDB ID: 6VW1) interaction site and 1,283 drugs FDA approved and prescribed by the Mexican Public Health System. The results were analyzed by docking score, frequency of the drug in receptor site and the types of interactions at the binding site residues. Results: About 40 drugs were identified as a potential inhibitor of RBD S1-ACE2 interaction. Within the top-ranked drugs, we identified ipratropium, formoterol and fexofenadine, which stands out as they are used as therapies to treat chronic obstructive pulmonary disease, asthma and virtually any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.

The UMAG_00031 gene from Ustilago maydis encodes a putative membrane protein involved in pH control and morphogenesis.

We report the characterization of the gene UMAG_00031 from Ustilago maydis, previously identified as upregulated at alkaline pH. This gene is located on chromosome 1 and contains an ORF of 1539 bp that encodes a putative protein of 512 amino acids with an MW of 54.8 kDa. The protein is predicted to contain seven transmembrane domains (TMDs) and a signal peptide suggesting that is located in the cell membrane. Null ΔUMAG_00031 mutants were constructed, and their phenotype was analyzed. The mutant displayed a pleiotropic phenotype suggesting its participation in processes of alkaline pH adaptation independent of the Pal/Rim pathway. Also, it was involved in the dimorphic process induced by fatty acids. These results indicate that the protein encoded by the UMAG_00031 gene possibly functions as a receptor of different signals in the cell membrane of the fungus.

Properties of a Non-canonical Complex Formed Between a Tepary Bean (Phaseolus acutifolius) Protease Inhibitor and α-Chymotrypsin.

Protease inhibitors are crucial for the control of proteolytic activity in different physiological processes. However, some inhibitors do not show canonical enzyme recognition of the enzyme under certain conditions. In this work, we present evidence that indicates the formation of an active complex between the protease bovine α-chymotrypsin and the Tepary bean protease inhibitor (TBPI). The composition of the active chymotrypsin-TBPI complex (AC) was confirmed by three different methods: size-exclusion chromatography, polyacrylamide gel electrophoresis (PAGE), and mass spectrometry. The kinetic parameters for the AC were similar to those of the enzyme alone, indicating that TBPI binding does not produce any large changes in chymotrypsin. The molecular model proposed here postulates that TBPI binds outside the active cleft of the protease, but near enough to hinder the binding of high molecular weight substrates into the active site. This model was experimentally supported by the inhibitory effect on casein as a substrate, and the unaltered protease activity when a small synthetic substrate was used. We also found that the formation of this complex provided the enzyme with extra stability in denaturing conditions or in the presence of a reducing agent. The chymotrypsin-TBPI complex exhibited higher stability, indicating that autolysis can be partially prevented. When the enzyme was first inactivated followed by the addition of the inhibitor, the activity of the protease was restored. We described a possible mechanism where a plant protease inhibitor binds outside the active site of the enzyme while increasing its stability.