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Structure. 2018 Aug 7;26(8):1137-1143.e3. doi: 10.1016/j.str.2018.05.008. Epub 2018 Jun 28.

Structural Basis for MARK1 Kinase Autoinhibition by Its KA1 Domain.

Author information

1
Department of Biochemistry and Biophysics and the Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: emptage@upenn.edu.
2
Department of Pharmacology and Cancer Biology Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Department of Biochemistry and Biophysics and the Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: marmor@upenn.edu.

Abstract

The kinase associated-1 (KA1) domain is found at the C-terminus of multiple Ser/Thr protein kinases from yeast to humans, and has been assigned autoinhibitory, membrane-binding, and substrate-targeting roles. Here, we report the crystal structure of the MARK1 kinase/UBA domain bound to its autoinhibitory KA1 domain, revealing an unexpected interface at the αD helix and contacts with both the N- and C-lobes of the kinase domain. We confirm the binding interface location in kinetic studies of variants mutated on the kinase domain surface. Together with other MARK kinase structures, the data implicate that the KA1 domain blocks peptide substrate binding. The structure highlights the kinase-specific autoinhibitory binding modes of different KA1 domains, and provides potential new avenues by which to intervene therapeutically in Alzheimer's disease and cancers in which MARK1 or related kinases are implicated.

KEYWORDS:

C-terminal domain; MARK1; Tau protein; activation segment; autoinhibition; inhibitory mechanism; serine/threonine protein kinase; structural biology; αD helix

PMID:
30099988
PMCID:
PMC6092042
DOI:
10.1016/j.str.2018.05.008
[Indexed for MEDLINE]
Free PMC Article

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