Motifs and structural fold of the cofactor binding site of human glutamate decarboxylase

Protein Science - Tập 7 Số 5 - Trang 1092-1105 - 1998
Kunbin Qu1, David L. Martin2, Charles E. Lawrence1,3
1Biometrics Laboratory, New York State Department of Health, Albany, New York 12201
2Laboratory of Nervous System Disorders, Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 12201
3National Center for Biotechnology Information, National Library of Medicine, National Institute of Health, Bethesda, Maryland 20894

Tóm tắt

AbstractThe pyridoxal‐P binding sites of the two isoforms of human glutamate decarboxylase (GAD65 and GAD67) were modeled by using PROBE (a recently developed algorithm for multiple sequence alignment and database searching) to align the primary sequence of GAD with pyridoxal‐P binding proteins of known structure. GAD's cofactor binding site is particularly interesting because GAD activity in the brain is controlled in part by a regulated interconversion of the apo‐ and holoenzymes. PROBE identified six motifs shared by the two GADs and four proteins of known structure: bacterial ornithine decarboxylase, dialkylglycine decarboxylase, aspartate aminotransferase, and tyrosine phenol‐lyase. Five of the motifs corresponded to the α/β elements and loops that form most of the conserved fold of the pyridoxal‐P binding cleft of the four enzymes of known structure; the sixth motif corresponded to a helical element of the small domain that closes when the substrate binds. Eight residues that interact with pyridoxal‐P and a ninth residue that lies at the interface of the large and small domains were also identified. Eleven additional conserved residues were identified and their functions were evaluated by examining the proteins of known structure. The key residues that interact directly with pyridoxal‐P were identical in ornithine decarboxylase and the two GADs, thus allowing us to make a specific structural prediction of the cofactor binding site of GAD. The strong conservation of the cofactor binding site in GAD indicates that the highly regulated transition between apo‐ and holoGAD is accomplished by modifications in this basic fold rather than through a novel folding pattern.

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Tài liệu tham khảo

10.1111/j.1432-1033.1994.tb18577.x

10.1021/bi00067a006

10.1006/geno.1994.1246

10.1083/jcb.118.2.309

10.1006/jmbi.1996.0508

10.1074/jbc.270.5.2241

10.1016/0896-6273(91)90077-D

10.1016/S0959-440X(96)80058-3

10.1073/pnas.94.10.4866

10.1038/273443a0

10.1016/0167-4838(95)00025-P

10.2337/diabetes.41.10.1355

10.1126/science.8211139

10.1016/0022-2836(92)90964-L

10.1016/S0022-2836(83)80129-6

LiuJS LawrenceCE.1996.Statistical models for multiple sequence alignment: Unifications and generalizations.Proc Am Stat Assoc Stat Comput Sect:1–8.

10.1080/01621459.1995.10476622

LiuJS NeuwaldA LawrenceCE.1998.Markovian structures in biological sequence alignments.JASAForthcoming.

MartinDL BarkeK.1997.Are GAD65and GAD67associated with specific pools of GABA in brain?Perspect Dev Biol. Forthcoming.

10.1523/JNEUROSCI.11-09-02725.1991

10.1111/j.1471-4159.1993.tb03165.x

10.1016/0022-2836(92)90935-D

10.1016/0022-2836(92)90691-C

10.1111/j.1432-1033.1993.tb17953.x

10.1006/jmbi.1995.0526

10.1002/pro.5560040504

10.1074/jbc.272.3.1548

10.1002/pro.5560040820

10.1093/nar/25.9.1665

10.1016/0014-5793(93)80314-K

10.1111/j.1432-1033.1991.tb15821.x

10.1111/j.1471-4159.1988.tb01173.x

10.1042/bj2310705

10.1093/nar/18.20.6097

10.1046/j.1471-4159.1996.66052082.x

10.1073/pnas.90.7.3073

10.1083/jcb.126.2.331

10.1016/B978-0-08-040820-0.50025-X

10.1006/jmbi.1994.0014

Watanabe N, 1991, Enzymes dependent on pyridoxal phosphate and other carbonyl compounds as cofactors

Xlook Version 2.0.1996.Product of Molecular Application Group Palo Alto.

ZhuJ LiuJS LawrenceCE.1997.Bayesian alignment and inference.ISMB‐975:358–368.

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Protein Science

Tập 7 Số 5

1092-1105

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