@article{2ed37f6b4ede4cb79eef3ec0d94a97d4,
title = "Structural basis for autoinhibition of the guanine nucleotide exchange factor FARP2",
abstract = "FARP2 is a Dbl-family guanine nucleotide exchange factor (GEF) that contains a 4.1, ezrin, radixin and moesin (FERM) domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. FARP2 activates Rac1 or Cdc42 in response to upstream signals, thereby regulating processes such as neuronal axon guidance and bone homeostasis. How the GEF activity of FARP2 is regulated remained poorly understood. We have determined the crystal structures of the catalytic DH domain and the DH-PH-PH domains of FARP2. The structures reveal an auto-inhibited conformation in which the GEF substrate-binding site is blocked collectively by the last helix in the DH domain and the two PH domains. This conformation is stabilized by multiple interactions among the domains and two well-structured inter-domain linkers. Our cell-based activity assays confirm the suppression of the FARP2 GEF activity by these auto-inhibitory elements.",
author = "Xiaojing He and Kuo, {Yi Chun} and Rosche, {Tyler J.} and Xuewu Zhang",
note = "Funding Information: We thank Paul Sternweis and members in the Zhang laboratory for discussions and technical assistance, Michael Rosen for the SopE protein, John Sondek for some of the RhoGTPase plasmids, and David King for mass spectrometry. We also thank the staff at the structural biology laboratory at University of Texas Southwestern (UTSW) and at beamline 19ID of Argonne National Laboratory (APS) for assistance with X-ray data collection. X.Z. is a Virginia Murchison Linthicum Scholar in Medical Research at UTSW. The work is supported in part by grants to X.Z. from the American Heart Association (10GRNT3430013), National Institute of General Medical Sciences (5R01GM088197), and the Welch foundation (I-1702). Use of the beamline at the structural biology center at APS was supported by the United States DOE under contract DE-AC02-06CH11357. X.Z. and X.H. conceived the project; X.H. and X.Z. determined the structures; Y.-C.K. performed the cell-based assays; X.H. and Y.-C.K. performed the in vitro GEF assays; T.R. optimized the protein purification procedure; and X.Z., X.H., and Y.-C.K. wrote the paper. ",
year = "2013",
month = mar,
day = "5",
doi = "10.1016/j.str.2013.01.001",
language = "English (US)",
volume = "21",
pages = "355--364",
journal = "Structure",
issn = "0969-2126",
publisher = "Cell Press",
number = "3",
}