Cullin neddylation may allosterically tune polyubiquitin chain length and topology

Melis Onel, Fidan Sumbul, Jin Liu, Ruth Nussinov, Turkan Haliloglu

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5CTD) and Rbx1 (Cul5CTD residues R538/R569 and Rbx1 residue E67, or Cul5CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets.

Original languageEnglish
Pages (from-to)781-795
Number of pages15
JournalBiochemical Journal
Volume474
Issue number5
DOIs
StatePublished - 1 Mar 2017

Fingerprint

Cullin Proteins
Polyubiquitin
Chain length
Ubiquitin-Protein Ligases
Ubiquitination
Topology
Substrates
Hinges
Proteins
Molecular Dynamics Simulation
Molecular dynamics
Hydrogen
Carrier Proteins
Hydrogen bonds
Communication
Computer simulation
Pharmaceutical Preparations

Cite this

Onel, Melis ; Sumbul, Fidan ; Liu, Jin ; Nussinov, Ruth ; Haliloglu, Turkan. / Cullin neddylation may allosterically tune polyubiquitin chain length and topology. In: Biochemical Journal. 2017 ; Vol. 474, No. 5. pp. 781-795.
@article{8881dcfd478e4a7bbb5f512d46369413,
title = "Cullin neddylation may allosterically tune polyubiquitin chain length and topology",
abstract = "Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5CTD) and Rbx1 (Cul5CTD residues R538/R569 and Rbx1 residue E67, or Cul5CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets.",
author = "Melis Onel and Fidan Sumbul and Jin Liu and Ruth Nussinov and Turkan Haliloglu",
year = "2017",
month = "3",
day = "1",
doi = "10.1042/BCJ20160748",
language = "English",
volume = "474",
pages = "781--795",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "5",

}

Cullin neddylation may allosterically tune polyubiquitin chain length and topology. / Onel, Melis; Sumbul, Fidan; Liu, Jin; Nussinov, Ruth; Haliloglu, Turkan.

In: Biochemical Journal, Vol. 474, No. 5, 01.03.2017, p. 781-795.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Cullin neddylation may allosterically tune polyubiquitin chain length and topology

AU - Onel, Melis

AU - Sumbul, Fidan

AU - Liu, Jin

AU - Nussinov, Ruth

AU - Haliloglu, Turkan

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5CTD) and Rbx1 (Cul5CTD residues R538/R569 and Rbx1 residue E67, or Cul5CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets.

AB - Conjugation of Nedd8 (neddylation) to Cullins (Cul) in Cul-RING E3 ligases (CRLs) stimulates ubiquitination and polyubiquitination of protein substrates. CRL is made up of two Cul-flanked arms: one consists of the substrate-binding and adaptor proteins and the other consists of E2 and Ring-box protein (Rbx). Polyubiquitin chain length and topology determine the substrate fate. Here, we ask how polyubiquitin chains are accommodated in the limited space available between the two arms and what determines the polyubiquitin linkage topology. We focus on Cul5 and Rbx1 in three states: before Cul5 neddylation (closed state), after neddylation (open state), and after deneddylation, exploiting molecular dynamics simulations and the Gaussian Network Model. We observe that regulation of substrate ubiquitination and polyubiquitination takes place through Rbx1 rotations, which are controlled by Nedd8-Rbx1 allosteric communication. Allosteric propagation proceeds from Nedd8 via Cul5 dynamic hinges and hydrogen bonds between the C-terminal domain of Cul5 (Cul5CTD) and Rbx1 (Cul5CTD residues R538/R569 and Rbx1 residue E67, or Cul5CTD E474/E478/N491 and Rbx1 K105). Importantly, at each ubiquitination step (homogeneous or heterogeneous, linear or branched), the polyubiquitin linkages fit into the distances between the two arms, and these match the inherent CRL conformational tendencies. Hinge sites may constitute drug targets.

UR - http://www.scopus.com/inward/record.url?scp=85014625617&partnerID=8YFLogxK

U2 - 10.1042/BCJ20160748

DO - 10.1042/BCJ20160748

M3 - Article

VL - 474

SP - 781

EP - 795

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 5

ER -