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SCFCdc4 (Skp1, Cdc53/cullin, F-box protein) defines a family of modular ubiquitin ligases (E3s) that regulate diverse processes including cell cycle, immune response, and development. Mass spectrometric analysis of proteins copurifying with Cdc53 identified the RING-H2 finger protein Hrt1 as a subunit of SCF. Hrt1 shows striking similarity to the Apc11 subunit of anaphase-promoting complex. Conditional inactivation of hrt1(ts) results in stabilization of the SCFCdc4 substrates Sic1 and Cln2 and cell cycle arrest at G1/S. Hrt1 assembles into recombinant SCF complexes and individually binds Cdc4, Cdc53 and Cdc34, but not Skp1. Hrt1 stimulates the E3 activity of recombinant SCF potently and enables the reconstitution of Cln2 ubiquitination by recombinant SCFGrr1. Surprisingly, SCF and the Cdc53/Hrt1 subcomplex activate autoubiquitination of Cdc34 E2 enzyme by a mechanism that does not appear to require a reactive thiol. The highly conserved human HRT1 complements the lethality of hrt1Delta, and human HRT2 binds CUL-1. We conclude that Cdc53/Hrt1 comprise a highly conserved module that serves as the functional core of a broad variety of heteromeric ubiquitin ligases.

Type

Journal article

Journal

Genes Dev

Publication Date

15/06/1999

Volume

13

Pages

1614 - 1626

Keywords

Amino Acid Sequence, Anaphase-Promoting Complex-Cyclosome, Animals, Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome, Basic Helix-Loop-Helix Transcription Factors, Binding Sites, Cell Cycle Proteins, Cullin Proteins, Enzyme Activation, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Humans, Ligases, Molecular Sequence Data, Recombinant Fusion Proteins, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, Saccharomyces cerevisiae Proteins, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases, Ubiquitins