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Structural Biology of CRL Ubiquitin Ligases

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Cullin-RING Ligases and Protein Neddylation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1217))

Abstract

Cullin-RING ubiquitin ligases (CRLs) represent the largest superfamily of multi-subunit E3s conserved in all eukaryotes. Soon after the discovery of these important ubiquitin ligase machineries, structural studies have made tremendous contributions to our understanding of their functions. Identification of the key components of CRLs by early studies raised immediate questions as to how these multi-subunit complexes assemble to promote the polyubiquitination of substrates. Specifically, how do the CRL subunits interact with each other to form a versatile E3 platform? How do they recognize specific substrates? How are the CRL-substrate interactions regulated in response to upstream signals? How are the CRL E3s themselves activated and deactivated, and how are substrate receptor subunits of CRLs exchanged in the cell? Even though we might not yet have complete answers to these questions, extensive structural analyses of CRL complexes in the past two decades have begun to unveil the themes and variations of CRL biology. In this chapter we will discuss both classic and emerging structures that help elucidate the overall architecture of CRLs, their substrate recognition modes, and regulatory mechanism of CRLs by NEDD8 modification.

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Abbreviations

APOBEC3:

Apolipoprotein B mRNA editing enzyme

catalytic polypeptide-like 3

ARIH1:

Ariadne-1 homolog

ASK1:

Apoptosis signal-regulating kinase 1

AUX/IAA:

Auxin/indole-3-acetic acid

BPA:

Beta-propeller A

BPB:

Beta-propeller B

BPC:

Beta-propeller C

BTB:

Broad-complex, tramtrack, and bric-a-brac

CAND1:

Cullin-associated NEDD8-dissociated protein 1

CBF-β:

Core-binding factor beta

CDC34:

Cell division cycle 34/ubiquitin-conjugating enzyme E3 R1

CDK2:

Cyclin-dependent kinase 2

CK1α:

Casein kinase 1

CKS1:

Cyclin-dependent kinases regulatory subunit 1

COI1:

Coronatine-insensitive protein 1

COP9:

Constitutive photomorphogenesis 9

CRBN:

Cereblon

CRL:

Cullin-RING ubiquitin ligases

CRY1/2:

Cryptochrome circadian regulator 1/2

CSN:

COP9 signalosome

CTD:

C-terminal domain

CUL:

Cullin

DCAFs:

DDB1-CUL4A-associated factors

DCN1:

Defective in cullin neddylation protein 1-like protein 1

DDB1/2:

DNA damage-binding protein 1/2

EB:

Elongin B

EC:

Elongin C

FBXL:

F-box and leucine-rich repeat proteins

FBXO:

F-box and other repeat-containing proteins

FBXW:

F-box and WD repeat-containing proteins

GLMN:

Glomulin

GSPT1:

G1 to S phase transition 1

HHARI/ARIH1:

Ariadne-1 homolog

HIF1α:

Hypoxia-inducible factor 1 subunit alpha

IKZF1/3:

IKAROS family zinc finger 1/3

IP6:

Inositol hexakisphosphate

JA:

Jasmonic acid

JAZ:

Jasmonate ZIM domain

KEAP1:

Kelch-like ECH-associated protein 1

KLHDC2:

Kelch domain-containing protein 2

LRR:

Leucine-rich repeat

MATH:

Meprin and TRAF-C homology

MEIS2:

Myeloid ecotropic viral integration site 1 homolog 2

NEDD8:

Neural precursor cell-expressed developmentally downregulated protein 8

NRF2:

Nuclear factor erythroid 2-related factor 2

NTD:

N-terminal domain

ODD:

Oxygen-dependent degradation

PTM:

Post-translational modification

RBX1/2:

RING box protein 1/2

RING:

Really interesting new genes

RING-IBR-RING RBR:

RING – in between ring – RING

SALL4:

Sal-like protein 4

SCF:

SKP1, CUL1, and F-box proteins

SELK:

Selenoprotein K

SELS:

Selenoprotein S

SKP1/2:

S-phase kinase-associated protein 1/2

SPOP:

Speckle-type POZ protein

STAT:

Signal transducer and activator of transcription

SV5-V:

Simian virus 5 V protein

TIR1:

Transport inhibitor response 1

UBC12/UBE2M:

Ubiquitin-conjugating enzyme E2 M

USP1:

Ubiquitin specific peptidase 1

VHL:

von Hippel-Lindau tumor suppressor

Vif:

Viral infectivity factor

WHB:

Winged-helix B

Wnt:

Wingless

β-TrCP:

Beta-transducin repeat-containing Protein

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Acknowledgments

We thank all members of the Zheng laboratory for their support and help. We apologize to all colleagues whose work could not be cited due to space constraints and the timing of manuscript preparation. Both D-V.R. and N.Z. are supported by Howard Hughes Medical Institute. N.Z. is a Howard Hughes Medical Institute Investigator.

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Authors and Affiliations

  1. Department of Pharmacology, University of Washington, Seattle, WA, USA

    Domnița-Valeria Rusnac & Ning Zheng

  2. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA

    Ning Zheng

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  1. Domnița-Valeria Rusnac
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  2. Ning Zheng
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Correspondence to Ning Zheng .

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Editors and Affiliations

  1. Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Yi Sun

  2. Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Wenyi Wei

  3. Life Science Institute, Zhejiang University, Hangzhou, China

    Jianping Jin

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Rusnac, DV., Zheng, N. (2020). Structural Biology of CRL Ubiquitin Ligases. In: Sun, Y., Wei, W., Jin, J. (eds) Cullin-RING Ligases and Protein Neddylation. Advances in Experimental Medicine and Biology, vol 1217. Springer, Singapore. https://doi.org/10.1007/978-981-15-1025-0_2

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