Triple-helical ligands selectively targeting the closed αI domain of integrin α2β1
Year: 2026
Type: article
Abstract: Integrins α1β1, α2β1, α10β1, and α11β1 are known to recognize the GxxGEx motif of the collagen triple helix through their αI domains, with the Glu residue engaging the domain via a divalent metal cation. The binding amino acid sequences containing these motifs, identified from native collagen, exhibit low subtype selectivity. Here we identify novel triple-helical peptides that selectively bind the α2I domain independently of Glu and metal ions. Yeast two-hybrid screening of randomized triple-helical peptide libraries yielded non-natural sequences in which the canonical Glu was replaced by aliphatic residues such as Met. X-ray crystal structural analysis of the representative variant GFOGMR in complex with the α2I domain revealed a new binding mode. In this mode, peptides are recognized by the closed, inactive conformation of the α2I domain without metal coordination. This cryptic interaction, likely unused by native ligands, provides a new basis for the design of subtype-specific ligands targeting collagen-binding integrins.
Source: Journal of Biological Chemistry
Institutions: Waseda University, Research Institute for Microbial Diseases, The University of Osaka, The University of Osaka, Osaka Metropolitan University, National Cerebral and Cardiovascular Center, National Cerebral and Cardiovascular Center Research Institute, National Cerebral and Cardiovascular Center Hospital, Waseda Research Institute for Science and Engineering
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
OpenAlex ID: W7223239821