4GZL

Crystal structure of RAC1 Q61L mutant

Summary for 4GZL

• Entry DOI: 10.2210/pdb4gzl/pdb
• Related: 3SBD 3SBE 3TH5 4GZM
• Descriptor: Ras-related C3 botulinum toxin substrate 1, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: rossmann fold, gtp binding, membrane, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side (By similarity): P63000
• Total number of polymer chains: 2
• Total formula weight: 46591.24

Authors

Ha, B.H.,Boggon, T.J. (deposition date: 2012-09-06, release date: 2012-12-12, Last modification date: 2023-09-13)

Primary citation

Davis, M.J.,Ha, B.H.,Holman, E.C.,Halaban, R.,Schlessinger, J.,Boggon, T.J.
RAC1P29S is a spontaneously activating cancer-associated GTPase.
Proc.Natl.Acad.Sci.USA, 110:912-917, 2013

PubMed Abstract: RAC1 is a small, Ras-related GTPase that was recently reported to harbor a recurrent UV-induced signature mutation in melanoma, resulting in substitution of P29 to serine (RAC1(P29S)), ranking this the third most frequently occurring gain-of-function mutation in melanoma. Although the Ras family GTPases are mutated in about 30% of all cancers, mutations in the Rho family GTPases have rarely been observed. In this study, we demonstrate that unlike oncogenic Ras proteins, which are primarily activated by mutations that eliminate GTPase activity, the activated melanoma RAC1(P29S) protein maintains intrinsic GTP hydrolysis and is spontaneously activated by substantially increased inherent GDP/GTP nucleotide exchange. Determination and comparison of crystal structures for activated RAC1 GTPases suggest that RAC1(F28L)--a known spontaneously activated RAC1 mutant--and RAC1(P29S) are self-activated in distinct fashions. Moreover, the mechanism of RAC1(P29S) and RAC1(F28L) activation differs from the common oncogenic mutations found in Ras-like GTPases that abrogate GTP hydrolysis. The melanoma RAC1(P29S) gain-of-function point mutation therefore represents a previously undescribed class of cancer-related GTPase activity.

PubMed: 23284172
DOI: 10.1073/pnas.1220895110

Experimental method

X-RAY DIFFRACTION (2 Å)