Structure of the human Tim44 C-terminal domain in complex with pentaethylene glycol: ligand-bound form

Noriko Handa; Seiichiro Kishishita; Satoshi Morita; Ryogo Akasaka; Zhongmin Jin; John Chrzas; Lirong Chen; Zhi-Jie Liu; Bi-Cheng Wang; Sumio Sugano; Akiko Tanaka; Takaho Terada; Mikako Shirouzu; Shigeyuki Yokoyama

doi:10.1107/S0907444907051463

Structure of the human Tim44 C-terminal domain in complex with pentaethylene glycol: ligand-bound form

Acta Crystallogr D Biol Crystallogr. 2007 Dec;63(Pt 12):1225-34. doi: 10.1107/S0907444907051463. Epub 2007 Nov 16.

Authors

Noriko Handa¹, Seiichiro Kishishita, Satoshi Morita, Ryogo Akasaka, Zhongmin Jin, John Chrzas, Lirong Chen, Zhi-Jie Liu, Bi-Cheng Wang, Sumio Sugano, Akiko Tanaka, Takaho Terada, Mikako Shirouzu, Shigeyuki Yokoyama

Affiliation

¹ Protein Research Group, Genomic Sciences Center, Yokohama Institute, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan.

PMID: 18084070
DOI: 10.1107/S0907444907051463

Abstract

Familial oncocytic thyroid carcinoma is associated with a missense mutation, P308Q, in the C-terminal domain of Tim44. Tim44 is the mitochondrial inner-membrane translocase subunit and it functions as a membrane anchor for the mitochondrial heat-shock protein 70 (mtHsp70). Here, the crystal structure of the human Tim44 C-terminal domain complexed with pentaethylene glycol has been determined at 1.9 A resolution. The overall structure resembles that of the nuclear transport factor 2-like domain. In the crystal structure, pentaethylene glycol molecules are associated at two potential membrane-binding sites: the large hydrophobic cavity and the highly conserved loop between the alpha1 and alpha2 helices near Pro308. A comparison with the yeast homolog revealed that lipid binding induces conformational changes around the alpha1-alpha2 loop, leading to slippage of the alpha1 helix along the large beta-sheet. These changes may play important roles in the translocation of polypeptides across the mitochondrial inner membrane.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Carrier Proteins / chemistry*
Carrier Proteins / genetics
Catalytic Domain
Crystallography, X-Ray
Humans
Membrane Proteins / chemistry*
Membrane Proteins / genetics
Mitochondrial Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
Mitochondrial Proteins / chemistry*
Mitochondrial Proteins / genetics
Models, Molecular
Mutation, Missense / genetics*
Polyethylene Glycols / chemistry*
Protein Binding
Protein Structure, Tertiary / genetics
Reactive Oxygen Species
Recombinant Proteins / chemistry*
Recombinant Proteins / genetics
Sequence Alignment
Structure-Activity Relationship
Thyroid Neoplasms / genetics
Thyroid Neoplasms / pathology

Substances

Carrier Proteins
Membrane Proteins
Mitochondrial Membrane Transport Proteins
Mitochondrial Precursor Protein Import Complex Proteins
Mitochondrial Proteins
Reactive Oxygen Species
Recombinant Proteins
TIMM44 protein, human
Polyethylene Glycols