TY - JOUR
T1 - Structural stabilization of GTP-binding domains in circularly permuted GTPases
T2 - Implications for RNA binding
AU - Anand, Baskaran
AU - Verma, Sunil Kumar
AU - Prakash, Balaji
N1 - Funding Information:
B.A. acknowledges AICTE (All India Council for Technical Education) for the National Doctoral Fellowship. SKV acknowledges UGC (University Grants Commission) for the Senior Research Fellowship. This work is supported by Wellcome Trust, UK (Grant No-GR-073616) in the form of an ‘International Senior Research Fellowship in Biomedical Science’ awarded to B.P. and grants from DST (Department of Science and Technology) and MHRD (Ministry of Human Resource and Development), India. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust, UK.
PY - 2006
Y1 - 2006
N2 - GTP hydrolysis by GTPases requires crucial residues embedded in a conserved G-domain as sequence motifs G1-G5. However, in some of the recently identified GTPases, the motif order is circularly permuted. All possible circular permutations were identified after artificially permuting the classical GTPases and subjecting them to profile Hidden Markov Model searches. This revealed G4-G5-G1-G2-G3 as the only possible circular permutation that can exist in nature. It was also possible to recognize a structural rationale for the absence of other permutations, which either destabilize the invariant GTPase fold or disrupt regions that provide critical residues for GTP binding and hydrolysis, such as Switch-I and Switch-II. The circular permutation relocates Switch-II to the C-terminus and leaves it unfastened, thus affecting GTP binding and hydrolysis. Stabilizing this region would require the presence of an additional domain following Switch-II. Circularly permuted GTPases (cpGTPases) conform to such a requirement and always possess an 'anchoring' C-terminal domain. There are four sub-families of cpGTPases, of which three possess an additional domain N-terminal to the G-domain. The biochemical function of these domains, based on available experimental reports and domain recognition analysis carried out here, are suggestive of RNA binding. The features that dictate RNA binding are unique to each subfamily. It is possible that RNA-binding modulates GTP binding or vice versa. In addition, phylogenetic analysis indicates a closer evolutionary relationship between cpGTPases and a set of universally conserved bacterial GTPases that bind the ribosome. It appears that cpGTPases are RNA-binding proteins possessing a means to relate GTP binding to RNA binding.
AB - GTP hydrolysis by GTPases requires crucial residues embedded in a conserved G-domain as sequence motifs G1-G5. However, in some of the recently identified GTPases, the motif order is circularly permuted. All possible circular permutations were identified after artificially permuting the classical GTPases and subjecting them to profile Hidden Markov Model searches. This revealed G4-G5-G1-G2-G3 as the only possible circular permutation that can exist in nature. It was also possible to recognize a structural rationale for the absence of other permutations, which either destabilize the invariant GTPase fold or disrupt regions that provide critical residues for GTP binding and hydrolysis, such as Switch-I and Switch-II. The circular permutation relocates Switch-II to the C-terminus and leaves it unfastened, thus affecting GTP binding and hydrolysis. Stabilizing this region would require the presence of an additional domain following Switch-II. Circularly permuted GTPases (cpGTPases) conform to such a requirement and always possess an 'anchoring' C-terminal domain. There are four sub-families of cpGTPases, of which three possess an additional domain N-terminal to the G-domain. The biochemical function of these domains, based on available experimental reports and domain recognition analysis carried out here, are suggestive of RNA binding. The features that dictate RNA binding are unique to each subfamily. It is possible that RNA-binding modulates GTP binding or vice versa. In addition, phylogenetic analysis indicates a closer evolutionary relationship between cpGTPases and a set of universally conserved bacterial GTPases that bind the ribosome. It appears that cpGTPases are RNA-binding proteins possessing a means to relate GTP binding to RNA binding.
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U2 - 10.1093/nar/gkl178
DO - 10.1093/nar/gkl178
M3 - Article
C2 - 16648363
AN - SCOPUS:33744528396
SN - 0305-1048
VL - 34
SP - 2196
EP - 2205
JO - Nucleic acids research
JF - Nucleic acids research
IS - 8
ER -