Structure of the human Tim44 C-terminal domain in complex with pentaethylene glycol: ligand-bound form.
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.
Handa
Noriko
N
Protein Research Group, Genomic Sciences Center, Yokohama Institute, RIKEN, 1-7-22 Suehiro, Tsurumi, Yokohama 230-0045, Japan.
Kishishita
Seiichiro
S
Morita
Satoshi
S
Akasaka
Ryogo
R
Jin
Zhongmin
Z
Chrzas
John
J
Chen
Lirong
L
Liu
Zhi-Jie
ZJ
Wang
Bi-Cheng
BC
Sugano
Sumio
S
Tanaka
Akiko
A
Terada
Takaho
T
Shirouzu
Mikako
M
Yokoyama
Shigeyuki
S
D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology
D002352:Carrier Proteins; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C489671:TIMM44 protein, human; D011092:Polyethylene Glycols