Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase

Joseph J. Rasimas; Paula A. Dalessio; Ira J. Ropson; Anthony E. Pegg; Michael G. Fried

doi:10.1110/ps.03319404

Active-site alkylation destabilizes human O⁶-alkylguanine DNA alkyltransferase

Joseph J. Rasimas, Paula A. Dalessio, Ira J. Ropson, Anthony E. Pegg, Michael G. Fried

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

O⁶-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O⁶-alkylguanine and O⁴-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5-1.2 kcal/mole and the DNA-binding function by 0.8-1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.

Original language	English (US)
Pages (from-to)	301-305
Number of pages	5
Journal	Protein Science
Volume	13
Issue number	1
DOIs	https://doi.org/10.1110/ps.03319404
State	Published - Jan 2004

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology

Access to Document

10.1110/ps.03319404

Cite this

@article{c973291b8a6845ef8f7ed454762c8cc0,

title = "Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase",

abstract = "O6-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O6-alkylguanine and O4-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5-1.2 kcal/mole and the DNA-binding function by 0.8-1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.",

author = "Rasimas, {Joseph J.} and Dalessio, {Paula A.} and Ropson, {Ira J.} and Pegg, {Anthony E.} and Fried, {Michael G.}",

year = "2004",

month = jan,

doi = "10.1110/ps.03319404",

language = "English (US)",

volume = "13",

pages = "301--305",

journal = "Protein Science",

issn = "0961-8368",

publisher = "Cold Spring Harbor Laboratory Press",

number = "1",

}

TY - JOUR

T1 - Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase

AU - Rasimas, Joseph J.

AU - Dalessio, Paula A.

AU - Ropson, Ira J.

AU - Pegg, Anthony E.

AU - Fried, Michael G.

PY - 2004/1

Y1 - 2004/1

N2 - O6-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O6-alkylguanine and O4-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5-1.2 kcal/mole and the DNA-binding function by 0.8-1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.

AB - O6-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O6-alkylguanine and O4-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5-1.2 kcal/mole and the DNA-binding function by 0.8-1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.

UR - http://www.scopus.com/inward/record.url?scp=0346733325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0346733325&partnerID=8YFLogxK

U2 - 10.1110/ps.03319404

DO - 10.1110/ps.03319404

M3 - Article

C2 - 14691244

AN - SCOPUS:0346733325

SN - 0961-8368

VL - 13

SP - 301

EP - 305

JO - Protein Science

JF - Protein Science

IS - 1

ER -

Active-site alkylation destabilizes human O⁶-alkylguanine DNA alkyltransferase

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this