2.4 Å resolution crystal structure of human TRAP1NM, the Hsp90 paralog in the mitochondrial matrix
Open accessAbstract
TRAP1 is an organelle-specific Hsp90 paralog that is essential for neoplastic growth. As a member of the Hsp90 family, TRAP1 is presumed to be a general chaperone facilitating the late-stage folding of Hsp90 client proteins in the mitochondrial matrix. Interestingly, TRAP1 cannot replace cytosolic Hsp90 in protein folding, and none of the known Hsp90 co-chaperones are found in mitochondria. Thus, the three-dimensional structure of TRAP1 must feature regulatory elements that are essential to the ATPase activity and chaperone function of TRAP1. Here, the crystal structure of a human TRAP1 NM dimer is presented, featuring an intact N-domain and M-domain structure, bound to adenosine 5′-β,γ-imidotriphosphate (ADPNP). The crystal structure together with epitope-mapping results shows that the TRAP1 M-domain loop 1 contacts the neighboring subunit and forms a previously unobserved third dimer interface that mediates the specific interaction with mitochondrial Hsp70.
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Sequence alignments show that interface I and II residues are generally conserved among Hsp90 and Hsp70 homologues and paralogues, suggesting a universal Hsp90-Hsp70 binding strategy across species and organelles.
“Finally, sequence alignments of Hsp90 and Hsp70 homologues and paralogues showed that interface I and II residues are generally conserved, suggesting a universal Hsp90–Hsp70 binding strategy across species23,24,27 and organelles28,29 (Supplementary Fig. 2a, b).”
From Structure of Hsp90–Hsp70–Hop–GR reveals the Hsp90 client-loading mechanism (2022) · cites this paper as [28]
Section 3.4 reports Hsp90–Hsp70 cooperation in mitochondrial, eukaryotic cytosolic, and prokaryotic systems, and a direct interaction between TRAP1 and mitochondrial Hsp70. It does not report sequence alignments showing conservation of interface I and II residues or establish a universal binding strategy; the section instead describes a specific TRAP1–mortalin interaction. Page numbers were not available in the indexed passages. (LLM, conf=0.82)
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References 31 · Cited by 15
Research works printed but not linked: 3
- Hattendorf, D. A. & Lindquist, S. (2002). Proc. Natl Acad. Sci. USA, 99, 2732-2737.
- Lee, J., Kim, J.-H., Biter, A. B., Sielaff, B., Lee, S. & Tsai, F. T. F. (2013). Proc. Natl Acad. Sci. USA, 110, 8513-8518.
- Sung, N., Lee, J., Kim, J.-H., Chang, C., Joachimiak, A., Lee, S. & Tsai, F. T. F. (2016). Proc. Natl Acad. Sci. USA, 113, 2952-2957.
- Authors
- Sung, N., Lee, J., Kim, J.-H., Chang, C., Tsai, F. T. F., & Lee, S.
- Affiliations
- Baylor College of Medicine (US)
- Argonne National Laboratory (US)
- Venue
- Acta Crystallographica Section D Structural Biology
- Published
- 2016-07-13
- Volume
- 72
- Issue
- 8
- Pages
- 904-911
- ISSN
- 2059-7983 (ISSN-L)
- PMC
- PMC4973209
- OpenAlex
- W2468432221
- Cited by
- 15
- References
- 31
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 3 · 2016: 1
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Acta Crystallographica Section D Structural Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, contract DE-AC02-06CH11357, 06CH11357, DE-AC02-)
- Welch Foundation (Q-1530)
- National Institutes of Health (DE-AC02–06CH11357, GM111084)
- National Institute of General Medical Sciences (R01GM104980, R01GM111084, R01GM115501)
- Biological and Environmental Research (DEAC0206CH11357)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- TRAP1, mitochondrial Hsp90, Hsp90 chaperone, mitochondrial matrix, ATPase activity, dimer interface, protein folding, crystal structure
- MeSH terms
- Protein Domains, Adenosine Triphosphate, Binding Sites, Humans, Mitochondria, Models, Molecular, Protein Conformation, Protein Folding, Crystallography, X-Ray, HSP90 Heat-Shock Proteins, Protein Multimerization
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