Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.

Chang, Y-G; Lupton, CJ; Bayly-Jones, C; Keen, AC; D'Andrea, L; Lucato, CM; Steele, JR; Venugopal, H; Schittenhelm, RB; Whisstock, JC; Halls, ML; Ellisdon, AM

Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.

Chang, Y-G Lupton, CJ Bayly-Jones, C Keen, AC D'Andrea, L Lucato, CM Steele, JR Venugopal, H Schittenhelm, RB Whisstock, JC Halls, ML Ellisdon, AM

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Nat Struct Mol Biol, 2022, 29, (8), pp. 767-773
Issue Date:: 2022-08

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Field	Value	Language
dc.contributor.author	Chang, Y-G
dc.contributor.author	Lupton, CJ
dc.contributor.author	Bayly-Jones, C
dc.contributor.author	Keen, AC
dc.contributor.author	D'Andrea, L
dc.contributor.author	Lucato, CM
dc.contributor.author	Steele, JR
dc.contributor.author	Venugopal, H
dc.contributor.author	Schittenhelm, RB
dc.contributor.author	Whisstock, JC
dc.contributor.author	Halls, ML
dc.contributor.author	Ellisdon, AM
dc.date.accessioned	2023-07-10T02:33:36Z
dc.date.available	2022-06-09
dc.date.available	2023-07-10T02:33:36Z
dc.date.issued	2022-08
dc.identifier.citation	Nat Struct Mol Biol, 2022, 29, (8), pp. 767-773
dc.identifier.issn	1545-9993
dc.identifier.issn	1545-9985
dc.identifier.uri	http://hdl.handle.net/10453/171392
dc.description.abstract	P-Rex (PI(3,4,5)P3-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by Gβγ and PI(3,4,5)P3 binding and dysregulated in cancer. Here, we use X-ray crystallography, cryogenic electron microscopy and crosslinking mass spectrometry to determine the structural basis of human P-Rex1 autoinhibition. P-Rex1 has a bipartite structure of N- and C-terminal modules connected by a C-terminal four-helix bundle that binds the N-terminal Pleckstrin homology (PH) domain. In the N-terminal module, the Dbl homology (DH) domain catalytic surface is occluded by the compact arrangement of the DH-PH-DEP1 domains. Structural analysis reveals a remarkable conformational transition to release autoinhibition, requiring a 126° opening of the DH domain hinge helix. The off-axis position of Gβγ and PI(3,4,5)P3 binding sites further suggests a counter-rotation of the P-Rex1 halves by 90° facilitates PH domain uncoupling from the four-helix bundle, releasing the autoinhibited DH domain to drive Rho GTPase signaling.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation.ispartof	Nat Struct Mol Biol
dc.relation.isbasedon	10.1038/s41594-022-00804-9
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences
dc.subject.classification	Biophysics
dc.subject.classification	Developmental Biology
dc.subject.classification	31 Biological sciences
dc.subject.classification	32 Biomedical and clinical sciences
dc.subject.classification	34 Chemical sciences
dc.subject.mesh	Binding Sites
dc.subject.mesh	Guanine Nucleotide Exchange Factors
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Neoplasms
dc.subject.mesh	Protein Domains
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasms
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Guanine Nucleotide Exchange Factors
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Binding Sites
dc.subject.mesh	Protein Domains
dc.subject.mesh	Binding Sites
dc.subject.mesh	Guanine Nucleotide Exchange Factors
dc.subject.mesh	Humans
dc.subject.mesh	Neoplasm Metastasis
dc.subject.mesh	Neoplasms
dc.subject.mesh	Protein Domains
dc.subject.mesh	Signal Transduction
dc.title	Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.
dc.type	Journal Article
utslib.citation.volume	29
utslib.location.activity	United States
utslib.for	03 Chemical Sciences
utslib.for	06 Biological Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Provost
pubs.organisational-group	/University of Technology Sydney/Provost/Jumbunna
utslib.copyright.status	open_access	*
dc.date.updated	2023-07-10T02:33:27Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	29
utslib.citation.issue	8

Abstract:

P-Rex (PI(3,4,5)P3-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by Gβγ and PI(3,4,5)P3 binding and dysregulated in cancer. Here, we use X-ray crystallography, cryogenic electron microscopy and crosslinking mass spectrometry to determine the structural basis of human P-Rex1 autoinhibition. P-Rex1 has a bipartite structure of N- and C-terminal modules connected by a C-terminal four-helix bundle that binds the N-terminal Pleckstrin homology (PH) domain. In the N-terminal module, the Dbl homology (DH) domain catalytic surface is occluded by the compact arrangement of the DH-PH-DEP1 domains. Structural analysis reveals a remarkable conformational transition to release autoinhibition, requiring a 126° opening of the DH domain hinge helix. The off-axis position of Gβγ and PI(3,4,5)P3 binding sites further suggests a counter-rotation of the P-Rex1 halves by 90° facilitates PH domain uncoupling from the four-helix bundle, releasing the autoinhibited DH domain to drive Rho GTPase signaling.

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http://hdl.handle.net/10453/171392