Near-Complete Structure and Model of Tel1ATM from Chaetomium thermophilum Reveals a Robust Autoinhibited ATP State

Jansma, Marijke; Linke-Winnebeck, Christian; Eustermann, Sebastian; Lammens, Katja; Kostrewa, Dirk; Stakyte, Kristina; Litz, Claudia; Kessler, Brigitte and Hopfner, Karl-Peter (2020): Near-Complete Structure and Model of Tel1ATM from Chaetomium thermophilum Reveals a Robust Autoinhibited ATP State. In: Structure, Vol. 28, No. 1: pp. 83-95

Abstract

Tel1 (ATM in humans) is a large kinase that resides in the cell in an autoinhibited dimeric state and upon activation orchestrates the cellular response to DNA damage. We report the structure of an endogenous Tell dimer from Chaetomium thermophilum. Major parts are at 2.8 angstrom resolution, including the kinase active site with ATP gamma S bound, and two different N-terminal solenoid conformations are at 3.4 angstrom and 3.6 angstrom, providing a side-chain model for 90% of the Tell polypeptide. We show that the N-terminal solenoid has DNA binding activity, but that its movements are not coupled to kinase activation. Although ATP gamma S and catalytic residues are poised for catalysis, the kinase resides in an autoinhibited state. The PIKK regulatory domain acts as a pseudo-substrate, blocking direct access to the site of catalysis. The structure allows mapping of human cancer mutations and defines mechanisms of autoinhibition at near-atomic resolution.

• Item Type: Journal article
• Faculties: Chemistry and Pharmacy > Department of Biochemistry
• Subjects: 500 Science > 540 Chemistry
• ISSN: 0969-2126
• Language: English