1ry7

From Proteopedia

Revision as of 11:57, 20 March 2008

Crystal Structure of the 3 Ig form of FGFR3c in complex with FGF1

Overview

The prototypical fibroblast growth factor receptor (FGFR) extracellular domain consists of three Ig domains (D1-D3) of which the two membrane-proximal D2 and D3 domains and the interconnecting D2-D3 linker bear the determinants of ligand binding and specificity. In contrast, D1 and the D1-D2 linker are thought to play autoinhibitory roles in FGFR regulation. Here, we report the crystal structure of the three-Ig form of FGFR3c in complex with FGF1, an FGF that binds promiscuously to each of the seven principal FGFRs. In this structure, D1 and the D1-D2 linker are completely disordered, demonstrating that these regions are dispensable for FGF binding. Real-time binding experiments using surface plasmon resonance show that relative to two-Ig form, the three-Ig form of FGFR3c exhibits lower affinity for both FGF1 and heparin. Importantly, we demonstrate that this autoinhibition is mediated by intramolecular interactions of D1 and the D1-D2 linker with the minimal FGF and heparin-binding D2-D3 region. As in the FGF1-FGFR2c structure, but not the FGF1-FGFR1c structure, the alternatively spliced betaC'-betaE loop is ordered and interacts with FGF1 in the FGF1-FGFR3c structure. However, in contrast to the FGF1-FGFR2c structure in which the betaC'-betaE loop interacts with the beta-trefoil core region of FGF1, in the FGF1-FGFR3c structure, this loop interacts extensively with the N-terminal region of FGF1, underscoring the importance of the FGF1 N terminus in conferring receptor-binding affinity and promiscuity. Importantly, comparison of the three FGF1-FGFR structures shows that the flexibility of the betaC'-betaE loop is a major determinant of ligand-binding specificity and promiscuity.

Disease

Known diseases associated with this structure: Achondroplasia OMIM:[134934], Aplasia of lacrimal and salivary glands OMIM:[602115], Bladder cancer OMIM:[134934], CATSHL syndrome OMIM:[134934], Cervical cancer, somatic OMIM:[134934], Colorectal cancer, somatic OMIM:[134934], Crouzon syndrome with acanthosis nigricans OMIM:[134934], Hypochondroplasia OMIM:[134934], LADD syndrome OMIM:[134934], LADD syndrome OMIM:[602115], Muenke syndrome OMIM:[134934], Nevus, keratinocytic, nonepidermolytic OMIM:[134934], Thanatophoric dysplasia, types I and II OMIM:[134934]

About this Structure

1RY7 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity., Olsen SK, Ibrahimi OA, Raucci A, Zhang F, Eliseenkova AV, Yayon A, Basilico C, Linhardt RJ, Schlessinger J, Mohammadi M, Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):935-40. Epub 2004 Jan 19. PMID:14732692

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