Abstract
Protein supra-domains are defined as recurring arrangements of two or three domains present adjacent to each other along a polypeptide chain. Such combinations have novel functions beyond those of the individual partner domains that compose them, which can exist in isolation. Here, we describe a new type of large supra-domain (~360 residues) in which one of the component partners (~200 residues) appears to be incapable of existing in a context other than immediately adjacent to the C-terminus of the well-characterized Hsp90-like ATPase domain. We found that this supra-domain has a broad phylogenetic distribution, with examples in Archaea, Bacteria, and Eukarya. There is strong selective pressure for this arrangement to occur as part of repeated regions of unprecedented length. We identified multiple strategies of convergent evolution to attain such configurations. In humans, this supra-domain is present in triplicate at the N-terminus of the protein sacsin (4579 residues), mutated in the neurodegenerative disorder known as spastic ataxia of Charlevoix-Saguenay, and thus, we termed it "sacsin repeating region" (SRR). Biochemical characterization demonstrated that SRRs possess ATPase activity, which appears to be a requirement for sacsin function, as a disease-causing mutation leads to an alternate conformation completely incapable of hydrolyzing ATP. We also found evidence of a convergent evolutionary strategy to place SRRs in proteins containing C-terminal J domains, which we demonstrated here to be capable of stimulating the intrinsic ATPase activity of Hsp70. Our sequence and biochemical analyses indicate that SRRs necessitate nucleotide hydrolysis for their function, provided by the common Hsp90 ATPase domain, which, when coupled to the unique adjacent sequence, may give rise to a novel activity related to protein quality control.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 665-674 |
| Number of pages | 10 |
| Journal | Journal of Molecular Biology |
| Volume | 400 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jul 2010 |
Fingerprint
Keywords
- Ataxia
- Molecular chaperone
- Protein folding
- Protein misfolding
- Protein supradomain
ASJC Scopus subject areas
- Molecular Biology
Cite this
The Sacsin Repeating Region (SRR) : A Novel Hsp90-Related Supra-Domain Associated with Neurodegeneration. / Anderson, John F.; Siller, Efrain; Barral, Jose M.
In: Journal of Molecular Biology, Vol. 400, No. 4, 07.2010, p. 665-674.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Sacsin Repeating Region (SRR)
T2 - A Novel Hsp90-Related Supra-Domain Associated with Neurodegeneration
AU - Anderson, John F.
AU - Siller, Efrain
AU - Barral, Jose M.
PY - 2010/7
Y1 - 2010/7
N2 - Protein supra-domains are defined as recurring arrangements of two or three domains present adjacent to each other along a polypeptide chain. Such combinations have novel functions beyond those of the individual partner domains that compose them, which can exist in isolation. Here, we describe a new type of large supra-domain (~360 residues) in which one of the component partners (~200 residues) appears to be incapable of existing in a context other than immediately adjacent to the C-terminus of the well-characterized Hsp90-like ATPase domain. We found that this supra-domain has a broad phylogenetic distribution, with examples in Archaea, Bacteria, and Eukarya. There is strong selective pressure for this arrangement to occur as part of repeated regions of unprecedented length. We identified multiple strategies of convergent evolution to attain such configurations. In humans, this supra-domain is present in triplicate at the N-terminus of the protein sacsin (4579 residues), mutated in the neurodegenerative disorder known as spastic ataxia of Charlevoix-Saguenay, and thus, we termed it "sacsin repeating region" (SRR). Biochemical characterization demonstrated that SRRs possess ATPase activity, which appears to be a requirement for sacsin function, as a disease-causing mutation leads to an alternate conformation completely incapable of hydrolyzing ATP. We also found evidence of a convergent evolutionary strategy to place SRRs in proteins containing C-terminal J domains, which we demonstrated here to be capable of stimulating the intrinsic ATPase activity of Hsp70. Our sequence and biochemical analyses indicate that SRRs necessitate nucleotide hydrolysis for their function, provided by the common Hsp90 ATPase domain, which, when coupled to the unique adjacent sequence, may give rise to a novel activity related to protein quality control.
AB - Protein supra-domains are defined as recurring arrangements of two or three domains present adjacent to each other along a polypeptide chain. Such combinations have novel functions beyond those of the individual partner domains that compose them, which can exist in isolation. Here, we describe a new type of large supra-domain (~360 residues) in which one of the component partners (~200 residues) appears to be incapable of existing in a context other than immediately adjacent to the C-terminus of the well-characterized Hsp90-like ATPase domain. We found that this supra-domain has a broad phylogenetic distribution, with examples in Archaea, Bacteria, and Eukarya. There is strong selective pressure for this arrangement to occur as part of repeated regions of unprecedented length. We identified multiple strategies of convergent evolution to attain such configurations. In humans, this supra-domain is present in triplicate at the N-terminus of the protein sacsin (4579 residues), mutated in the neurodegenerative disorder known as spastic ataxia of Charlevoix-Saguenay, and thus, we termed it "sacsin repeating region" (SRR). Biochemical characterization demonstrated that SRRs possess ATPase activity, which appears to be a requirement for sacsin function, as a disease-causing mutation leads to an alternate conformation completely incapable of hydrolyzing ATP. We also found evidence of a convergent evolutionary strategy to place SRRs in proteins containing C-terminal J domains, which we demonstrated here to be capable of stimulating the intrinsic ATPase activity of Hsp70. Our sequence and biochemical analyses indicate that SRRs necessitate nucleotide hydrolysis for their function, provided by the common Hsp90 ATPase domain, which, when coupled to the unique adjacent sequence, may give rise to a novel activity related to protein quality control.
KW - Ataxia
KW - Molecular chaperone
KW - Protein folding
KW - Protein misfolding
KW - Protein supradomain
UR - http://www.scopus.com/inward/record.url?scp=77954385279&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954385279&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2010.05.023
DO - 10.1016/j.jmb.2010.05.023
M3 - Article
C2 - 20488193
AN - SCOPUS:77954385279
VL - 400
SP - 665
EP - 674
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 4
ER -