The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Xu, Zhen; Gakhar, Lokesh; Bain, Fletcher E.; Spies, Maria; Fuentes, Ernesto J.

doi:10.1074/jbc.M117.799114

Title: The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

Journal Article · Thu Sep 07 00:00:00 EDT 2017 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M117.799114· OSTI ID:1432852

Xu, Zhen ^[1]; Gakhar, Lokesh ^[1]; Bain, Fletcher E. ^[1]; Spies, Maria ^[1];

^[1]

Univ. of Iowa, Iowa City, IA (United States)

T-cell lymphoma invasion and metastasis 1 (Tiam1) is a Dbl-family guanine nucleotide exchange factor (GEF) that specifically activates the Rho-family GTPase Rac1 in response to upstream signals, thereby regulating cellular processes including cell adhesion and migration. Tiam1 contains multiple domains, including an N-terminal pleckstrin homology coiled-coiled extension (PH_n-CC-Ex) and catalytic Dbl homology and C-terminal pleckstrin homology (DH-PH_c) domain. Previous studies indicate that larger fragments of Tiam1, such as the region encompassing the N-terminal to C-terminal pleckstrin homology domains (PH_n-PH_c), are auto-inhibited. However, the domains in this region responsible for inhibition remain unknown. Here, we show that the PH_n-CC-Ex domain inhibits Tiam1 GEF activity by directly interacting with the catalytic DH-PH_c domain, preventing Rac1 binding and activation. Enzyme kinetics experiments suggested that Tiam1 is auto-inhibited through occlusion of the catalytic site rather than by allostery. Small angle X-ray scattering and ensemble modeling yielded models of the PH_n-PH_c fragment that indicate it is in equilibrium between “open” and “closed” conformational states. Lastly, single-molecule experiments support a model in which conformational sampling between the open and closed states of Tiam1 contributes to Rac1 dissociation. Our results highlight the role of the PH_n-CC-Ex domain in Tiam1 GEF regulation and suggest a combinatorial model for GEF inhibition and activation of the Rac1 signaling pathway.

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Research Organization:: Bettis Atomic Power Lab. (BAPL), West Mifflin, PA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health; National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; R01 GM108617; MCB-0953080; NIH 5T32GM008365

OSTI ID:: 1432852

Journal Information:: Journal of Biological Chemistry, Vol. 292, Issue 43; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 9 works

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Title: The Tiam1 guanine nucleotide exchange factor is auto-inhibited by its pleckstrin homology coiled-coil extension domain

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