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E1 Ubiquitin/Ubl Activating Enzymes


Overview of E1 ubiquitin/Ubl activating enzymes

Ubiqutin (Ub) - and Ubiqutin-like (Ubl) - dependent metabolism is a multi-enzyme process involving the continuous activity of different ligases. E1 activating enzymes are the core of Ub/UBL conjugation in vivo and in vitro, because they initiate conjugation cascades by activating their respective modifiers.

These enzymes are parts of a larger E1-like superfamily of enzymes that include cysteine, thiamine, molybdenum cofactor (MoCo) and several secondary metabolites in biosynthesis. The basic catalytic mechanisms of these enzymes involve adenylation and sulfonyl transfer as well as specific domains and structures to determine the specificity of substrate binding and other related protein-protein interactions.

Ubiquitin-activating enzymes

Ubiquitin-activating enzymes, also known as E1 enzymes, are the ubiquitin activating enzymes in ubiquitin- proteasome pathway, which is the first step in catalytic ubiquitin cascade. It can load the ubiquitin and other protein ubiquitin samples to the target protein. This pathway is very important in human tissue cells which can do the energy dissipation and degradation to specific proteins. Covalent binding of ubiquitin or ubiquitin-like proteins to target proteins is the main mechanism regulating protein function in eukaryotes. Many processes such as cell division, immune response and embryonic development are also regulated by post-translational modifications of ubiquitin and ubiquitin-like proteins.

Role in ubiquitination

At the initial stage of ubiquitination, E1 enzyme binds with ATP and binds to ubiquitin protein. The E1 enzyme then passes ubiquitous proteins to a second protein, called ubiquitous protein carriers or conjugated proteins (E2). E2 protein is combined with ubiquitin protein ligase (E3). This ubiquitin protein ligase recognition needs to label protein and catalyze ubiquitin to the protein. The pathway repeats itself until the target protein has a complete ubiquitin chain linked to itself.

At the beginning of the ubiquitination cascade, E1 enzymes bind to ATP-Mg2+ and ubiquitin proteins and catalyze ubiquitin C-terminal adenylation. In the next step, the catalytic cysteine on the E1 enzyme attacks the ubiquitin-AMP complex through acyl substitution, producing thioester bonds and AMP leaving groups. Finally, E1-ubiquitin is transferred to E2 enzyme by transesterification of the protein complex, where E2 catalyzes cysteine to attack E1-ubiquitin on the back of the protein complex. However, the transport sulfation process is complex because both E1 and E2 enzymes form intermediate complexes, both of which undergo a series of conformational changes to bind to each other.

Related protein

Proteins

Description

UBA1

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene. UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes. This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.

UBA3

NEDD8-activating enzyme E1 catalytic subunit is a protein that in humans is encoded by the UBA3 gene. NEDD8 is a ubiquitin-like protein, which regulates cell division, signaling and embryogenesis.

UBA5

Ubiquitin-like modifier-activating enzyme 5 is a protein that in humans is encoded by the UBA5 gene. This gene encodes a member of the E1-like activating enzyme family. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

UBA7

Ubiquitin-like modifier-activating enzyme 7 is a protein that in humans is encoded by the UBA7 gene. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme is a retinoid target that triggers promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) degradation and apoptosis in acute promyelocytic leukemia.

ATG7

Autophagy-related protein 7 is a protein in humans encoded by ATG7 gene. ATG7, present in both plant and animal genomes, acts as an essential protein for cell degradation and its recycling. The sequence associates with the ubiquitin- proteasome system, UPS, required for the unique development of an autophagosomal membrane and fusion within cells.

NAE1

NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene. The protein encoded by this gene binds to the beta-amyloid precursor protein. In addition, the encoded protein can form a heterodimer with UBE1C and bind and activate NEDD8, a ubiquitin-like protein.

Role in disease

Ubiquitin proteasome system is essential for proper protein degradation in cells. Dysfunction of the system can destroy cell homeostasis and lead to many diseases. In normal functioning cells, ubiquitin or ubiquitin-like protein covalently linked to the target protein changes the surface of the target protein. These ubiquitin proteins are degraded by proteolysis and non-protein hydrolysis. If the system fails, it can lead to many inherited and acquired diseases, such as cancer, diabetes, stroke, amyotrophic lateral sclerosis, Alzheimer's disease, asthma, multiple sclerosis, autoimmune thyroiditis, inflammatory bowel disease, inflammatory arthritis and lupus.

References:

  1. Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. Journal of the American Society of Nephrology : JASN. July 2006, 17 (7): 1807–19.
  2. Lee I, Schindelin H. Structural insights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes. Cell. July 2008, 134 (2): 268–78.
  3. Johnson ES, Schwienhorst I, Dohmen RJ, et al. The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer. The EMBO Journal. 1997, 16 (18): 5509–19.

Bohnsack RN, Haas AL. Conservation in the mechanism of Nedd8 activation by the human AppBp1-Uba3 heterodimer. The Journal of Biological Chemistry. July 2003, 278 (29): 26823–30.

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