Cumulative phylogenetic, sequence and structural analysis of Insulin superfamily proteins provide unique structure-function insights.

Autor: Rao SS; Division of Biological Sciences, Poornaprajna Institute of Scientific Research, Poornaprajnapura, 562110, Bidalur (Post), Bengaluru, India.; Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India., Kundapura SV; Division of Biological Sciences, Poornaprajna Institute of Scientific Research, Poornaprajnapura, 562110, Bidalur (Post), Bengaluru, India.; Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India., Dey D; Division of Biological Sciences, Poornaprajna Institute of Scientific Research, Poornaprajnapura, 562110, Bidalur (Post), Bengaluru, India.; Present address: Department of Biochemistry, Emory University School of Medicine, GA 30322, Atlanta, USA., Palaniappan C; Department of Computational and Data Sciences, Indian Institute of Science, 560012, Bangalore, India.; Molecular Biophysics Unit, Indian Institute of Science, 560012, Bangalore, India., Sekar K; Department of Computational and Data Sciences, Indian Institute of Science, 560012, Bangalore, India., Kulal A; Division of Biological Sciences, Poornaprajna Institute of Scientific Research, Poornaprajnapura, 562110, Bidalur (Post), Bengaluru, India., Ramagopal UA; Division of Biological Sciences, Poornaprajna Institute of Scientific Research, Poornaprajnapura, 562110, Bidalur (Post), Bengaluru, India.; Department of Microbiology and FST, School of Science, GITAM University, 530045, Visakhapatnam, India.
Jazyk: angličtina
Zdroj: Molecular informatics [Mol Inform] 2024 Sep; Vol. 43 (9), pp. e202300160. Date of Electronic Publication: 2024 Jul 08.
DOI: 10.1002/minf.202300160
Abstrakt: The insulin superfamily proteins (ISPs), in particular, insulin, IGFs and relaxin proteins are key modulators of animal physiology. They are known to have evolved from the same ancestral gene and have diverged into proteins with varied sequences and distinct functions, but maintain a similar structural architecture stabilized by highly conserved disulphide bridges. The recent surge of sequence data and the structures of these proteins prompted a need for a comprehensive analysis, which connects the evolution of these sequences (427 sequences) in the light of available functional and structural information including representative complex structures of ISPs with their cognate receptors. This study reveals (a) unusually high sequence conservation of IGFs (>90 % conservation in 184 sequences) and provides a possible structure-based rationale for such high sequence conservation; (b) provides an updated definition of the receptor-binding signature motif of the functionally diverse relaxin family members (c) provides a probable non-canonical C-peptide cleavage site in a few insulin sequences. The high conservation of IGFs appears to represent a classic case of resistance to sequence diversity exerted by physiologically important interactions with multiple partners. We also propose a probable mechanism for C-peptide cleavage in a few distinct insulin sequences and redefine the receptor-binding signature motif of the relaxin family. Lastly, we provide a basis for minimally modified insulin mutants with potential therapeutic application, inspired by concomitant changes observed in other insulin superfamily protein members supported by molecular dynamics simulation.
(© 2024 The Authors. Molecular Informatics published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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