Neddylation (also NEDDylation) is the process by which the

ubiquitin-like protein Ubiquitin-like proteins (UBLs) are a family of small proteins involved in post-translational modification of other proteins in a cell, usually with a regulatory function. The UBL protein family derives its name from the first member of the class ...

NEDD8 NEDD8 is a protein that in humans is encoded by the ''NEDD8'' gene. (in ''saccharomyces cerevisiae'' this protein is known as Rub1) This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a proc ...

is conjugated to its target proteins. This process is analogous to

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

ation, although it relies on its own E1 and E2 enzymes. No NEDD8-specific E3 has yet been identified and it is possible that the Neddylation system relies on E3 ligases with dual specificity.

NEDD8

NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is a protein involved in the regulation of cell growth, viability and development.

Neddylation process

NEDD8 links itself to a protein through an isopeptide linkage between its carboxy-terminal glycine and the lysine of the substrate. The neddylation of the substrate causes in a structural change, and there are three main biochemical effects that result. First, neddylation can cause a conformational change in the substrate which may restrict molecular movement and the positioning of different binding partners. Second, it can cause the target protein to become incompatible with other proteins that it usually binds with. For example,

CAND1 Cullin-associated NEDD8-dissociated protein 1 is a protein that in humans is encoded by the ''CAND1'' gene. Interactions CAND1 has been shown to interact with: * CUL1, * CUL2, * CUL3, * CUL4A, * CUL4B, * DCUN1D1 DCN1-like protein 1 is a ...

does not bind to neddylated proteins. In addition, neddylation can recruit NEDD8-interacting proteins. When NEDD8 binds to the ubiquitin E2 Ubc4, the interaction stimulates

cullin Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form ''Cullin-RING ubiquitin ligases'' (CRLs) that are highly dive ...

-based ubiquitin ligases, although the exact mechanism is unclear.

Disease association

Neddylation is involved in the pathogenesis of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

where its activation appears to drive neurons into

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

by initiating

cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...

reentry. Also, evidence shows that increased NEDD8 conjugation in human oral carcinoma cells led to abnormal higher degrees of proliferation. Because NEDD8 conjugation to cullin proteins plays an important role in the regulation of the cell cycle, an upregulation in conjugation causes this proliferation.Chairatvit K, Ngamkitidechakul C. Control of cell proliferation via elevated NEDD8 conjugation in oral squamous cell carcinoma. Mol Cell Biochem. 2007;306(1-2):163-9.

References

External links

doi:10.1371/journal.pone.0043391 {{posttranslational modification Proteins Post-translational modification