Biology:WDR12

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Ribosome biogenesis protein WDR12 is a protein that in humans is encoded by the WDR12 gene on chromosome 2.[1][2][3] It is ubiquitously expressed in many tissues and cell types.[4] WDR12 participates in ribosome biogenesis and cell proliferation as a component of the PeBoW complex.[1] This protein is associated with cardiovascular diseases such as coronary artery disease and myocardial infarction.[5] The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[6]

Structure

Gene

The WDR12 gene resides on chromosome 2 at the band 2q33.2 and includes 13 exons.[3]

Protein

WDR12 is a member of the WD repeat WDR12/YTM1 family and contains 7 WD repeats.[7][1] Each WD repeat typically contains a C-terminal tryptophan-aspartic acid dipeptide and an N-terminal glycine-histidine dipeptide.[8] Disruption of these 7 WD repeats tampers with the predicted propeller-like structure formed and, consequently, its nucleolar localization.[1] At the N-terminus of WDR12 lies a ubiquitin-like (UBL) domain, which contains β-grasp fold similar to that found in ubiquitin. The UBL domain binds the motor protein midasin and facilitates release of the PeBoW complex, which is composed of WDR12, Pescadillo 1 (PES1), and Block of proliferation 1 (BOP1), from pre-ribosomal particles.[8][9]

Function

The WDR12 gene is ubiquitously expressed during embryogenesis, and high levels are found in the thymus and testis of adult mice.[1] It is a crucial factor in the mammalian ribosome biogenesis pathway that forms a stable complex named PeboW with Pes1 and Bop1.[1][2] WDR12 is required for processing of the 32S precursor rRNA without affecting the synthesis of the 45S/47S primary transcript and it functions in the maturation of the 60S ribosomal subunit. Depletion of WDR12 severely inhibits cell proliferation.[2] It is observed that WDR12 siRNA silencing in vitro resulted in decreased phosphorylation of p38 MAPK, HSP27, and ERK1/2 in neonatal myocytes, which may partially elucidate the mechanistic role of WDR12 in the regulation of cell proliferation, differentiation, and survival.[10][11] Given the evidence of in vitro binding of WDR12 to the cytoplasmic domain of Notch1, it is postulated that WDR12 also functions in the modulation of Notch signaling activity.[12]

Clinical significance

In humans, a large genome-wide association study (GWAS) identified several single nucleotide polymorphisms (SNPs) that were reproducible and strongly associated with a risk for coronary artery disease and myocardial infarction (i.e., heart attacks). In this large genetic study, a total of 46 genomic loci were linked to variations in susceptibility to coronary artery disease.[13] Within the 46 genome-wide SNPs, 12 indicated an association with a lipid levels and 5 showed significant association with high blood pressure. Accordingly, one of the most strongly associated variants was located on the WDR12 locus, which was also initially associated with the risk of early-onset myocardial infarction.[13] However, its exact cellular and functional role in the heart is still being identified.

Biomarker

The expression of WDR12 in the rat heart and the human heart was studied using WDR12 gene delivery to examine the direct functional and structural effects of WDR12 on cardiac maladaptive remodeling, in particular the left ventricle. This recent study revealed that overexpression of WDR12 by gene delivery could deteriorate both systolic and diastolic function of the rat heart. Likewise, subsequent analysis of a cohort of 1400 human subjects corroborated that the WDR12 variant was associated with diastolic dysfunction.[8]

Additionally, a multi-locus genetic risk score study, based on a combination of 27 loci including the WDR12 gene, identified individuals at increased risk for both incidence and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[6]

Interactions

Interactive Pathway Map

WDR12 participates in interactions within the major pathway of rRNA processing in the nucleolus.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Mammalian WDR12 is a novel member of the Pes1-Bop1 complex and is required for ribosome biogenesis and cell proliferation". The Journal of Cell Biology 170 (3): 367–78. August 2005. doi:10.1083/jcb.200501141. PMID 16043514. 
  2. ↑ 2.0 2.1 2.2 "Interdependence of Pes1, Bop1, and WDR12 controls nucleolar localization and assembly of the PeBoW complex required for maturation of the 60S ribosomal subunit". Molecular and Cellular Biology 27 (10): 3682–94. May 2007. doi:10.1128/MCB.00172-07. PMID 17353269. 
  3. ↑ 3.0 3.1 "Entrez Gene: WDR12 WD repeat domain 12". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55759. 
  4. ↑ "BioGPS - your Gene Portal System". http://biogps.org/#goto=genereport&id=55759. 
  5. ↑ "Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants". Nature Genetics 41 (3): 334–41. March 2009. doi:10.1038/ng.327. PMID 19198609. 
  6. ↑ 6.0 6.1 "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet 385 (9984): 2264–71. June 2015. doi:10.1016/S0140-6736(14)61730-X. PMID 25748612. 
  7. ↑ "WDR12 - Ribosome biogenesis protein WDR12 - Homo sapiens (Human) - WDR12 gene & protein". https://www.uniprot.org/uniprot/Q9GZL7. 
  8. ↑ 8.0 8.1 8.2 "WDR12, a Member of Nucleolar PeBoW-Complex, Is Up-Regulated in Failing Hearts and Causes Deterioration of Cardiac Function". PLOS ONE 10 (4): e0124907. 2015-01-01. doi:10.1371/journal.pone.0124907. PMID 25915632. Bibcode: 2015PLoSO..1024907M. 
  9. ↑ "The Crystal Structure of the Ubiquitin-like Domain of Ribosome Assembly Factor Ytm1 and Characterization of Its Interaction with the AAA-ATPase Midasin". The Journal of Biological Chemistry 291 (2): 882–93. January 2016. doi:10.1074/jbc.M115.693259. PMID 26601951. 
  10. ↑ "Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale". Physiological Reviews 90 (4): 1507–46. October 2010. doi:10.1152/physrev.00054.2009. PMID 20959622. 
  11. ↑ "Hold me tight: Role of the heat shock protein family of chaperones in cardiac disease". Circulation 122 (17): 1740–51. October 2010. doi:10.1161/CIRCULATIONAHA.110.942250. PMID 20975010. 
  12. ↑ "Wdr12, a mouse gene encoding a novel WD-Repeat Protein with a notchless-like amino-terminal domain". Genomics 79 (1): 77–86. January 2002. doi:10.1006/geno.2001.6682. PMID 11827460. 
  13. ↑ 13.0 13.1 "Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants". Nature Genetics 41 (3): 334–41. March 2009. doi:10.1038/ng.327. PMID 19198609. 

Further reading




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