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A Selection Fit Mechanism in BMP Receptor IA as a Possible Source for BMP Ligand-Receptor Promiscuity
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-68497
- Background: Members of the TGF-b superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity. Principal Findings:Background: Members of the TGF-b superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity. Principal Findings: In this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor’s BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical. Conclusions: Comparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors.…
Autor(en): | Stefan Harth, Alexander Kotzsch, Junli Hu, Walter Sebald, Thomas D. Mueller |
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URN: | urn:nbn:de:bvb:20-opus-68497 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Biologie / Julius-von-Sachs-Institut für Biowissenschaften |
Sprache der Veröffentlichung: | Englisch |
Erscheinungsjahr: | 2010 |
Originalveröffentlichung / Quelle: | PLOS ONE (2010) 5, 9, DOI: 10.1371/journal.pone.0013049 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 5 Naturwissenschaften und Mathematik / 58 Pflanzen (Botanik) / 580 Pflanzen (Botanik) |
Normierte Schlagworte (GND): | Physiologische Chemie |
Freie Schlagwort(e): | antigen binding antibody fragment (Fab) |
Datum der Freischaltung: | 18.03.2012 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung |