HSH2D

Hematopoietic SH2 Domain Containing (HSH2D) protein is a protein encoded by the hematopoietic SH2 domain containing (HSH2D) gene.

Gene

HSH2D is located on chromosome 19 at 19p13.11. Common aliases of the gene include HSH2 (Hematopoietic SH2 Protein) and ALX (Adaptor in Lymphocytes of Unknown Function X). The mRNA encodes two main isoforms. Isoform 1, the longest isoform, contains seven exons. The gene spans from 16134028 to 16158575.

mRNA

Two main isoforms of HSH2D exist. Isoform 1 has seven exons and is 2,403 bp in length. Isoform 2 has six exons and is 2,936 bp long. Although isoform 2 has longer mRNA, it still produces the smaller isoform in the mature protein. Isoform 2 has a variant 5’ UTR and a different start codon, as well as a shorter N-terminus.[1] The mRNA has a short 5' UTR and a long 3' UTR.

Protein

The protein has a molecular weight of 39.0 kilodaltons (kD) and a pI of 6.678.[2] The main feature of the protein is the SH2 (Src homology) domain, which is a region that has phosphotyrosine receptors and is important in many signaling molecules.[3] This domain is located from residues 26-127.

The secondary structure of the protein contains a helical section around residues 40-50, a sheet between 60-70, helices between 100-110, 135-145, 175-180, 200-225, and additional sheets between 235-240 and 295-300, shown in the figure at the bottom of the section (helices are purple arrows and sheets are red arrows). The protein has several locations of post-translational modifications, especially phosphorylation and GalNAc O-glycosylation, which has been shown to play a role in cancers.[4]

Predicted 3D structure of the HSH2D protein

The tertiary structure of the protein has not been confirmed through research, however, predictions using I-TASSER[5] software are useful in visualizing the protein.

Expression

Based on NCBI GEO[6] expression profiles and EST analyses, the protein appears to be narrowly expressed throughout human tissues. It is highly expressed in bone marrow, CD4+ and CD8+ T cells, lymph node, mammary gland, spleen, stomach, thyroid, and small intestine tissue. Expression is elevated in cases of early T-cell precursor acute lymphoblastic leukemia[6] and lowered in breast cancer cells that are treated with estrogen, suggesting an interaction between the protein and estrogen.

Function

The function of the HSH2D protein is still not fully understood, however it has been shown to play a role in various cellular functions such as apoptosis, wound healing, vascular endothelial growth factors, membrane-associated intracellular trafficking, biogenesis of lipid droplets and collagen remodeling.[7] It is also thought to play a role in T-cell activation.[8]

Interacting proteins

HSH2D interacts with several proto-oncogenes, including FES proto-oncogene (FES) and CRK proto-oncogene (CRK). It also has suspected interactions with other proteins such as tyrosine kinase non-receptor 2 (TRK2), PTEN-induced putative kinase (PINK1), and Interleukin 2 (IL2).[9] A summary of these proteins is shown below with their suspected functions.

Name NCBI Accession Number Function
FES proto-oncogene (FES) NP_001996.1 Hematopoiesis, growth factor and cytokine receptor signaling.
CRK proto-oncogene (CRK) NP_058431.2 Adaptor that binds to tyrosine-phosphorylated proteins. Has SH2 and SH3 domains
Tyrosine kinase non-receptor 2 (TNK2) NP_005772.3 Tyrosine kinase which may be linked to tyrosine phosphorylation signal transduction pathways.[10]
PTEN-induced putative kinase (PINK1) NP_115785.1 Serine/threonine protein kinase
Interleukin 2 (IL2) NP_000577.2 Cytokine important for T- and B- cell proliferation[11]

Clinical significance

The HSH2D protein has been studied along other human genes predicted to be involved in the human immune system. HSH2D was found to be highly expressed in patients with ulcerative colitis.[12] The protein is also associated with alpha-interferon activity.[13]

Homology

HSH2D has four distant paralogs and several orthologs in other species that have high levels of conservation.

Paralogs

The four paralogs of HSH2D in humans are other proteins containing SH2 domains. They do not have a high level of conservation other than this domain. All paralogs were found through genecards[14]

Name NCBI Accession Number Sequence Length (Amino Acids) Sequence Similarity Sequence Identity
SH2D2A NP_001154913.1 399 29%

21.7%

SH2D7 NP_001094874.1 451 33.1% 25.9%
SH2D4A NP_001167630.1 454 12% 17.4%
SH2D4B NP_997255.2 357 33.7% 18.1%

Orthologs

HSH2D has several orthologous proteins that span across several orders of species. The protein was well conserved across mammals as well as a few reptiles, amphibians, and invertebrates. The following list is not exhaustive, rather, it shows the wide range of organisms that the protein may be found in. All orthologous proteins were found with BLAST[15] or BLAT[16] programs.

Scientific Name Common Name Order NCBI Accession Number Sequence Length (Amino Acids) Sequence Identity Sequence Similarity
Pan troglodytes Chimpanzee Primates NP_001229302.1 352 99% 99.70%
Heterocephalus glaber Naked Mole Rat Rodentia EHB15865.1 324 54% 63.40%
Hipposideros armiger Great roundleaf bat Chiroptera XP_019497370.1 360 67% 76.10%
Condylura cristata Star nosed mole Soricomorpha XP_004688256.1 355 62% 72.10%
Camelus dromedarius Dromedary camel Cetariodactyla XP_010993355.1 360 66% 75.70%
Panthera pardus Leopard Carnivora XP_019271712.1 360 62% 71.40%
Meleagris gallopavo Wild Turkey Bird XP_010723595.1 326 23% 28.80%
Anolis carolinensis Carolina anole Reptile XP_016854511.1 567 22% 31.50%
Xenopus tropicalis Western clawed frog Amphibian XP_012809627.1 363 31% 42.80%
Callorhinchus milii Australian Ghostshark Fish XP_007899329.1 500 26% 33.10%
Lingula anatina Lingula Invertebrate XP_013404014.1 187 18% 23.40%
Biomphalaria glabrata N/A Invertebrate XP_013080865.1 818 12% 10.10%
Salpingoeca rosetta N/A Protista XP_004995081.1 481 17.70% 10.90%

References
  1. "hematopoietic SH2 domain containing [ Homo sapiens (human) ]". National Center for Biotechnology Information. 2017-04-22.
  2. Brendel, V., Bucher, P., Nourbakhsh, I.R., Blaisdell, B.E. & Karlin, S. (1992) "Methods and algorithms for statistical analysis of protein sequences" Proc. Natl. Sci. U.S.A 89, 2009-2006
  3. Filippakopoulos, Panagis (December 2009). "SH2 domains: modulators of nonreceptor tyrosine kinase activity". Current Opinion in Structural Biology. 19 (6): 643–649. doi:10.1016/j.sbi.2009.10.001. PMC 2791838. PMID 19926274.
  4. Gill, D. J. (March 2011). "Location, location, location: New insights into O-GalNAc protein glycosylation". Trends in Cell Biology. 21 (3): 149–158. doi:10.1016/j.tcb.2010.11.004. PMID 21145746.
  5. "I-TASSER".
  6. "NCBI GEO".
  7. Mackintosh, C.G (2016). "SOLiD SAGE sequencing shows differential gene expression in jejunal lymph node samples of resistant and susceptible red deer (Cervus elaphus) challenged with Mycobacterium avium subsp. Paratuberculosis". Veterinary Immunology and Immunopathology. 169: 102–110. doi:10.1016/j.vetimm.2015.10.009. PMID 26620077.
  8. Tatebe, Ken (2010). "Response network analysis of differential gene expression in human epithelial lung cells during avian influenza infections". BMC Bioinformatics. 11: 170. doi:10.1186/1471-2105-11-170. PMC 2868837. PMID 20370926.
  9. "STRING: Protein-Protein Interaction Network".
  10. "TNK2 tyrosine kinase non receptor 2".
  11. "IL2 Interleukin 2".
  12. Clark, Peter (2012). "Bioinformatics analysis reveals transcriptome and microRNA signatures and drug repositioning targets for IBD and other autoimmune diseases". Inflammatory Bowel Diseases. 18 (12): 2315–33. doi:10.1002/ibd.22958. PMID 22488912. S2CID 4629313.
  13. Schmeisser, H (2010). "Identification of Alpha Interferon-Induced Genes Associated with Antiviral Activity in Daudi Cells and Characterization of IFIT3 as a Novel Antiviral Gene". Journal of Virology. 84 (20): 10671–0680. doi:10.1128/jvi.00818-10. PMC 2950578. PMID 20686046.
  14. "HSH2D Gene".
  15. "NCBI BLAST".
  16. "UCSC BLAT Genome Search".
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