Allosteric mechanism for site-specific ubiquitination of FANCD2

Viduth K. Chaugule (Lead / Corresponding author), Connor Arkinson, Martin L. Rennie, Outi Kämäräinen, Rachel Toth, Helen Walden (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

DNA-damage repair is implemented by proteins that are coordinated by specialized molecular signals. One such signal in the Fanconi anemia (FA) pathway for the repair of DNA interstrand crosslinks is the site-specific monoubiquitination of FANCD2 and FANCI. The signal is mediated by a multiprotein FA core complex (FA-CC) however, the mechanics for precise ubiquitination remain elusive. We show that FANCL, the RING-bearing module in FA-CC, allosterically activates its cognate ubiqutin-conjugating enzyme E2 UBE2T to drive site-specific FANCD2 ubiquitination. Unlike typical RING E3 ligases, FANCL catalyzes ubiquitination by rewiring the intraresidue network of UBE2T to influence the active site. Consequently, a basic triad unique to UBE2T engages a structured acidic patch near the target lysine on FANCD2. This three-dimensional complementarity, between the E2 active site and substrate surface, induced by FANCL is central to site-specific monoubiquitination in the FA pathway. Furthermore, the allosteric network of UBE2T can be engineered to enhance FANCL-catalyzed FANCD2–FANCI di-monoubiquitination without compromising site specificity.

Original languageEnglish
JournalNature Chemical Biology
Early online date23 Dec 2019
DOIs
Publication statusE-pub ahead of print - 23 Dec 2019

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Allosteric Site
Fanconi Anemia
Ubiquitination
DNA Repair
Catalytic Domain
Ubiquitin-Protein Ligases
Mechanics
Lysine
DNA Damage
Enzymes
Proteins

Cite this

Chaugule, Viduth K. ; Arkinson, Connor ; Rennie, Martin L. ; Kämäräinen, Outi ; Toth, Rachel ; Walden, Helen. / Allosteric mechanism for site-specific ubiquitination of FANCD2. In: Nature Chemical Biology. 2019.
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Allosteric mechanism for site-specific ubiquitination of FANCD2. / Chaugule, Viduth K. (Lead / Corresponding author); Arkinson, Connor; Rennie, Martin L.; Kämäräinen, Outi; Toth, Rachel; Walden, Helen (Lead / Corresponding author).

In: Nature Chemical Biology, 23.12.2019.

Research output: Contribution to journalArticle

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