title: Understanding the specificity of serpin-protease complexes through interface analysis.
abstract: Serpins such as antithrombin, heparin cofactor II, plasminogen activator inhibitor, antitrypsin, antichymotrypsin, and neuroserpin are involved in important biological processes by inhibiting specific serine proteases. Initially, the protease recognizes the mobile reactive loop of the serpin eliciting conformational changes, where the cleaved loop together with the protease inserts into β-sheet A, translocating the protease to the opposite side of inhibitor leading to its inactivation. Serpin interaction with proteases is governed mainly by the reactive center loop residues (RCL). However, in some inhibitory serpins, exosite residues apart from RCL have been shown to confer protease specificity. Further, this forms the basis of multi-specificity of some serpins, but the residues and their dimension at interface in serpin-protease complexes remain elusive. Here, we present a comprehensive structural analysis of the serpin-protease interfaces using bio COmplexes COntact MAPS (COCOMAPS), PRotein Interface Conservation and Energetics (PRICE), and ProFace programs. We have carried out interface, burial, and evolutionary analysis of different serpin-protease complexes. Among the studied complexes, non-inhibitory serpins exhibit larger interface region with greater number of residue involvement as compared to the inhibitory serpins. On comparing the multi-specific serpins (antithrombin and antitrypsin), a difference in the interface area and residue number was observed, suggestive of a differential mechanism of action of these serpins in regulating their different target proteases. Further, detailed study of these multi-specific serpins listed few essential residues (common in all the complexes) and certain specificity (unique to each complex) determining residues at their interfaces. Structural mapping of interface residues suggested that individual patches with evolutionary conserved residues in specific serpins determine their specificity towards a particular protease.
authors: a Protein Conformation and Enzymology Lab, Department of Biosciences , Jamia Millia Islamia (A Central University) , New Delhi 110025 , India.
authors: Qudsia
authors: Q
authors: Rashid
authors: Charu
authors: C
authors: Kapil
authors: Poonam
authors: P
authors: Singh
authors: Vineeta
authors: V
authors: Kumari
authors: Mohamad Aman
authors: MA
authors: Jairajpuri
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids; D001665:Binding Sites; D030541:Databases, Genetic; D066264:Datasets as Topic; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D056510:Position-Specific Scoring Matrices; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D015843:Serpins / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D015843:Serpins; D010450:Endopeptidases
keywords: exosite; interface; patch; serine protease; serpins