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Cooperative fluctuations and subunit communication in tryptophan synthase.
Biochemistry. 1999 Mar 23; 38(12):3478-90.B

Abstract

Tryptophan synthase (TRPS), with linearly arrayed subunits alphabetabetaalpha, catalyzes the last two reactions in the biosynthesis of L-tryptophan. The two reactions take place in the respective alpha- and beta-subunits of the enzyme, and the intermediate product, indole, is transferred from the alpha- to the beta-site through a 25 A long hydrophobic tunnel. The occurrence of a unique ligand-mediated long-range cooperativity for substrate channeling, and a quest to understand the mechanism of allosteric control and coordination in metabolic cycles, have motivated many experimental studies on the structure and catalytic activity of the TRPS alpha2beta2 complex and its mutants. The dynamics of these complexes are analyzed here using a simple but rigorous theoretical approach, the Gaussian network model. Both wild-type and mutant structures, in the unliganded and various liganded forms, are considered. The substrate binding site in the beta-subunit is found to be closely coupled to a group of hinge residues (beta77-beta89 and beta376-beta379) near the beta-beta interface. These residues simultaneously control the anticorrelated motion of the two beta-subunits, and the opening or closing of the hydrophobic tunnel. The latter process is achieved by the large amplitude fluctuations of the so-called COMM domain in the same subunit. Intersubunit communications are strengthened in the presence of external aldimines bound to the beta-site. The motions of the COMM core residues are coordinated with those of the alpha-beta hinge residues beta174-beta179 on the interfacial helix betaH6 at the entrance of the hydrophobic tunnel. And the motions of betaH6 are coupled, via helix betaH1 and alphaL6, to those of the loop alphaL2 that includes the alpha-subunit catalytically active residue Asp60. Overall, our analysis sheds light on the molecular machinery underlying subunit communication, and identifies the residues playing a key role in the cooperative transmission of conformational motions across the two reaction sites.

Authors+Show Affiliations

Bahar I
Molecular Structure Section, Laboratory of Experimental and Computational Biology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5677, USA.
Jernigan RL
No affiliation info available

MeSH

Allosteric RegulationBinding SitesCatalysisCrystallography, X-RayLigandsModels, MolecularProtein ConformationProtein FoldingSalmonella typhimuriumSubstrate SpecificityTryptophan Synthase

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10090734

Citation

Bahar, I, and R L. Jernigan. "Cooperative Fluctuations and Subunit Communication in Tryptophan Synthase." Biochemistry, vol. 38, no. 12, 1999, pp. 3478-90.
Bahar I, Jernigan RL. Cooperative fluctuations and subunit communication in tryptophan synthase. Biochemistry. 1999;38(12):3478-90.
Bahar, I., & Jernigan, R. L. (1999). Cooperative fluctuations and subunit communication in tryptophan synthase. Biochemistry, 38(12), 3478-90.
Bahar I, Jernigan RL. Cooperative Fluctuations and Subunit Communication in Tryptophan Synthase. Biochemistry. 1999 Mar 23;38(12):3478-90. PubMed PMID: 10090734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cooperative fluctuations and subunit communication in tryptophan synthase. AU - Bahar,I, AU - Jernigan,R L, PY - 1999/3/26/pubmed PY - 1999/3/26/medline PY - 1999/3/26/entrez SP - 3478 EP - 90 JF - Biochemistry JO - Biochemistry VL - 38 IS - 12 N2 - Tryptophan synthase (TRPS), with linearly arrayed subunits alphabetabetaalpha, catalyzes the last two reactions in the biosynthesis of L-tryptophan. The two reactions take place in the respective alpha- and beta-subunits of the enzyme, and the intermediate product, indole, is transferred from the alpha- to the beta-site through a 25 A long hydrophobic tunnel. The occurrence of a unique ligand-mediated long-range cooperativity for substrate channeling, and a quest to understand the mechanism of allosteric control and coordination in metabolic cycles, have motivated many experimental studies on the structure and catalytic activity of the TRPS alpha2beta2 complex and its mutants. The dynamics of these complexes are analyzed here using a simple but rigorous theoretical approach, the Gaussian network model. Both wild-type and mutant structures, in the unliganded and various liganded forms, are considered. The substrate binding site in the beta-subunit is found to be closely coupled to a group of hinge residues (beta77-beta89 and beta376-beta379) near the beta-beta interface. These residues simultaneously control the anticorrelated motion of the two beta-subunits, and the opening or closing of the hydrophobic tunnel. The latter process is achieved by the large amplitude fluctuations of the so-called COMM domain in the same subunit. Intersubunit communications are strengthened in the presence of external aldimines bound to the beta-site. The motions of the COMM core residues are coordinated with those of the alpha-beta hinge residues beta174-beta179 on the interfacial helix betaH6 at the entrance of the hydrophobic tunnel. And the motions of betaH6 are coupled, via helix betaH1 and alphaL6, to those of the loop alphaL2 that includes the alpha-subunit catalytically active residue Asp60. Overall, our analysis sheds light on the molecular machinery underlying subunit communication, and identifies the residues playing a key role in the cooperative transmission of conformational motions across the two reaction sites. SN - 0006-2960 UR - https://www.unboundmedicine.com/medline/citation/10090734/Cooperative_fluctuations_and_subunit_communication_in_tryptophan_synthase_ L2 - https://doi.org/10.1021/bi982697v DB - PRIME DP - Unbound Medicine ER -