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A structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family.

ABSTRACT: Eukaryotic deubiquitinases are important regulators of ubiquitin signaling and can be subdivided into several structurally distinct classes. The ZUFSP family, with ZUP1 as its sole human member, has a modular architecture with a core catalytic domain highly active against the ubiquitin-derived peptide RLRGG, but not against ubiquitin itself. Ubiquitin recognition is conferred by additional non-catalytic domains, making full-length ZUP1 active against long K63-linked chains. However, non-mammalian ZUFSP family members contain different ubiquitin-binding domains in their N-terminal regions, despite their high conservation within the catalytic domain. Here, by working with representative ZUFSP family members from insects, fungi and plants, we show that different N-terminal domains are associated with different linkage preferences. Biochemical and structural studies suggest that the acquisition of two family-specific proximal domains have changed the default K48 preference of the ZUFSP family to the K63 preference observed in ZUP1 and its insect homolog. Additional N-terminal zinc finger domains promote chain cleavage without changing linkage-specificity.

SUBMITTER: Hermanns T

PROVIDER: S-EPMC8776766 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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A structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family.

Hermanns Thomas T Pichlo Christian C Baumann Ulrich U Hofmann Kay K

Nature communications 20220120 1

Eukaryotic deubiquitinases are important regulators of ubiquitin signaling and can be subdivided into several structurally distinct classes. The ZUFSP family, with ZUP1 as its sole human member, has a modular architecture with a core catalytic domain highly active against the ubiquitin-derived peptide RLRGG, but not against ubiquitin itself. Ubiquitin recognition is conferred by additional non-catalytic domains, making full-length ZUP1 active against long K63-linked chains. However, non-mammalia ...[more]

PMID: 35058438

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A structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family.

Publications

A structural basis for the diverse linkage specificities within the ZUFSP deubiquitinase family.

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