E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene. [5] [6] The SMURF1 Gene encodes a protein with a size of 757 amino acids and the molecular mass of this protein is 86114 Da. [7]
E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene. [5] [6] The SMURF1 Gene encodes a protein with a size of 757 amino acids and the molecular mass of this protein is 86114 Da. [7]
Smad ubiquitination regulatory factor 1 (Smurf1) is part of a gene that encodes a ubiquitin ligase and is specific for receptor-regulated SMAD proteins in the bone morphogenetic protein (BMP) pathway.
A similar protein in Xenopus is involved in embryonic pattern formation. Alternative splicing results in multiple transcript variants encoding different isoforms. An additional transcript variant has been identified, but its full length sequence has not been determined. [6]
The inhibition of HIV-1 replication in HeLa P4/R5 cells can be achieved by siRNA-mediated knockdown of SMURF1. [8]
SMURF1 and SMURF2 have shown to exhibit E3 ligase-dependent and E3 ligase-independent activities in a multitude of different cell types whereby smurfs can act as tumor promoters or tumor suppressors by regulating biological tumorigenesis-related processes. Recent research in breast cancer explains a relationship between SMURF1 and ER alpha (Estrogen receptor alpha) during breast cancer growth. Since ER alpha is expressed in most breast cancers and is attributed to contributing to the progression of estrogen-dependent cancer, it has been supported that the reduction of SMURF1 decreases the proliferation of ER alpha-positive cells in vitro and in vivo. [9] Thus, it is feasible that targeting SMURF1 may become a potential therapy for ER alpha-positive breast cancer.
Smurf1 may the potential to act as an oncogenic factor in other essential organs of the body. For instance, high levels of SMURF1’s are linked to low survival rates of patients who are diagnosed with gastric cancer (GC) and clear cell renal cell carcinoma (ccRCC). Similarly to the suppression of SMURF1 to possibly treat breast cancer, the inhibition of Smurf1 can decrease tumorigenesis in various types of digestive cancer cell models like pancreatic and gastric cancers. [10]
Continued research shows that SMURF1 can also been linked to various diseases. The downregulation of SMURF1 expression has been observed in neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Research is showing that SMURF1 plays a role in neuronal necroptosis whereby the up-regulation of Smurf1 was observed in the brain cortex of adult rats who experienced neuroinflammation, and Smurf1 knockdown with siRNA inhibited neuronal necroptosis. [11] This suggests that Smurf1 may promote neuronal necroptosis in neuroinflammatory conditions.
SMURF1 expression was increased in brain tissue samples from Parkinson's disease patients compared to controls, and that this increase was positively correlated with the accumulation of α-synuclein aggregates. Furthermore, the overexpression of SMURF1 in cultured cells led to increased levels of α-synuclein aggregates, while knockdown of SMURF1 reduced α-synuclein aggregation. [12] In the context of neurodegeneration, SMURF1 has been implicated in the regulation of protein quality control mechanisms such as autophagy and the ubiquitin-proteasome system, which are critical for the clearance of misfolded or aggregated proteins that can contribute to disease pathogenesis.
While the exact mechanisms by which SMURF1 contributes to neurodegenerative disorders are still not fully understood, there is growing evidence, research studies may suggest that SMURF1 may be a potential target for therapeutic intervention in protein aggregation and improving cellular proteostasis in neurodegenerative diseases. [13]
Under the influence of NDFIP1, it undergoes auto-ubiquitination. The SMURF1 protein is modified by the SCF(FBXL15) complex at two lysine residues, Lys-381 and Lys-383, which leads to its degradation by the proteasome. Whereby, Lys-383 is the primary site of ubiquitination. [14]
Smurfs are composed of several distinct domains that include an N-terminal C2 domain, two to three WW domains containing tryptophan residues, and an HECT domain. The C2 domain plays a crucial role in mediating the interaction of Smurfs with intracellular membranes. On the other hand, the WW domains of Smurfs are typically involved in protein-protein interactions, allowing them to interact with various target proteins. [15] SMURF1 has been shown to interact with:
Ubiquitin is a small 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. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.
A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.
Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.
Mothers against decapentaplegic homolog 2, also known as SMAD family member 2 or SMAD2, is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.
Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.
The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.
ITCH is a HECT domain–containing E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. The ITCH gene is located on chromosome 20 in humans. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.
S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene.
E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.
Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.
Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene. As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation. The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.
Ubiquitin D is a protein that in humans is encoded by the UBD gene, also known as FAT10. UBD acts like ubiquitin, by covalently modifying proteins and tagging them for destruction in the proteasome.
Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.
Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.
Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.
E3 ubiquitin-protein ligase SMURF2 is an enzyme that in humans is encoded by the SMURF2 gene which is located at chromosome 17q23.3-q24.1.
Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.
NEDD4-like E3 ubiquitin-protein ligase WWP2 also known as atrophin-1-interacting protein 2 (AIP2) or WW domain-containing protein 2 (WWP2) is an enzyme that in humans is encoded by the WWP2 gene.
βTrCP2 is a protein that in humans is encoded by the FBXW11 gene.