LRRIQ3 explained

LRRIQ3 (Leucine-rich repeats and IQ motif containing 3), which is also known as LRRC44, is a protein that in humans is encoded by the LRRIQ3 gene.^[1] It is predominantly expressed in the testes, and is linked to a number of diseases.^[2]

Gene

Locus

LRRIQ3 is found on the minus strand of the end of the short arm of human chromosome 1 at 1p31.1.^[3]

Overall Structure

There are a total of 7 exons in the putative sequence of LRRIQ3.

mRNA

Expression

LRRIQ3 is expressed as 2 primary isoforms, which produce proteins of length 624 amino acids and 464 amino acids respectively. It is expressed at low levels in human and brown rat tissues,^{[4] [5]} with highest expression levels in testes tissue. There are relatively high expression levels in T cells, the epididymis, the kidney, and a number of glands.^[6]

Protein

General Characteristics and Compositional Features

Human protein LRRIQ3 Isoform 1 consists of 624 amino acids, and has a molecular weight of 73.7 kDa. The isoelectric point of LRRIQ3 is 9.73, which suggests that LRRIQ3 is basic at normal physiological pH (~7.4).^[7] Additionally, there is strong evidence that human LRRIQ3 localizes to the plasma membrane from antibody staining.^[8] LRRIQ3 is rich in lysine residues, with a total of 82 lysines. It is also slightly low on glycines.^[9]

Domains and Motifs

In total, there are 4 conserved domains within LRRIQ3: 3 leucine-rich repeats and 1 IQ calmodulin-binding motif. Leucine-rich repeats are typically involved in protein-protein interactions, and form a characteristic α/β horseshoe fold.^{[10] [11]} An IQ motif provides a binding site for calmodulin (CaM) or CaM-like proteins.^[12]

Secondary and Tertiary Structure

LRRIQ3 is predicted to be mostly alpha-helical in structure, including a long alpha-helical C-terminal domain. It is also predicted to function as a monomer.^{[13] [14] [15] [16]}

Post-translational Modifications

LRRIQ3 is predicted to undergo many post-translational modifications. These include O-GlcNAcylation, SUMOylation, ubiquitination, and phosphorylation.^{[17] [18]} LRRIQ3 is predicted to have 4 well conserved SUMOylation sites and 1 well conserved ubiquitination site.^[17] A representation of these post-translational modifications is shown in the figure below.

Protein Interactions

There is evidence that LRRIQ3 interacts with a number of proteins from two-hybrid assays and affinity chromatography. The proteins LRRIQ3 interact with include LYN, NCK2, GNB4, and ABL1.^{[19] [20]} These proteins are associated with cell signalling, cytoskeletal reorganization, and cell differentiation, as well as others.^{[21] [22] [23] [24]}

Homology and evolution

Paralogs and Orthologs

No paralogs exists for LRRIQ3 in humans. However, there are a number of orthologs, as reported by BLAST, some of which are listed below.^[25] The number of years since divergence from the human protein, listed in "million of years ago (MYA)" below, were calculated using TimeTree.^[26]

Orthologs to Human LRRIQ3 Protein (NP_001099129.1)!Genus and Species!Common Name!Divergence from Human Lineage (MYA)!Accession Number!Sequence length (aa)!Sequence Identity to Human Protein!Sequence Similarity to Human Protein

Gorilla gorilla gorilla	Gorilla	9.06	XP_004026030.1	624	97%	98%
Macaca mulatta	Rhesus monkey	29.44	XP_001097148.2	623	93%	95%
Ursus maritimus	Polar bear	96	XP_008689049.1	625	76%	87%
Felis catus	Domestic cat	96	XP_003990274.1	625	74%	86%
Camelus ferus	Bactrian camel	96	XP_006178380.1	618	73%	84%
Oryctolagus cuniculus	European rabbit	90	XP_002715603.1	622	71%	83%
Bison bison bison	American bison	96	XP_010847739.1	625	70%	82%
Trichechus manatus latirostris	Manatee	105	XP_004369192.1	623	70%	82%
Loxodonta africana	African elephant	105	XP_003411181.1	625	68%	80%
Condylura cristata	Star-nosed mole	96	XP_004679575.1	627	67%	80%
Eptesicus fuscus	Big brown bat	96	XP_008137759.1	621	66%	80%
Myotis davidii	Vesper bat	96	XP_006775977.1	618	65%	79%
Rattus norvegicus	Norway rat	90	NP_001019478.1	633	62%	77%
Mus Musculus	House mouse	90	NP_083214.2	633	63%	76%
Sorex araneus	Common shrew	96	XP_004603704.1	612	55%	73%
Chrysemys picta bellii	Painted turtle	312	XP_005285573.1	624	40%	56%
Pogona vitticeps	Bearded dragon	312	XP_020650341.1	651	35%	54%
Apteryx australis mantelli	Brown kiwi	312	XP_013800580.1	664	35%	54%
Struthio camelus australis	Southern Ostrich	312	XP_009685099.1	628	34%	51%

Clinical significance

LRRIQ3 is linked to a number of cancers. RNA-seq experiments have shown that LRRIQ3 is severely down-regulated (Log₂-fold changes between -3.4 and -4.2) in a number of disease states, including pancreatic cancer, colorectal cancer, and breast cancer.^{[27] [28] [29]}

Notes and References

1. Web site: LRRIQ3 Gene - GeneCards.
2. Web site: AceView entry on LRRIQ3.
3. Web site: LRRIQ3 leucine rich repeats and IQ motif containing 3 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2018-04-30.
4. Web site: Lrriq3 protein abundance in PaxDb. pax-db.org. en. 2018-04-30.
5. Web site: LRRIQ3 protein abundance in PaxDb. pax-db.org. en. 2018-04-30.
6. Web site: GDS3834 / 3169. www.ncbi.nlm.nih.gov. 2018-05-06.
7. Web site: ExPASy - Compute pI/Mw tool. web.expasy.org. en-US. 2018-04-30.
8. Web site: Cell atlas - LRRIQ3 - The Human Protein Atlas. www.proteinatlas.org. 2018-04-30.
9. Web site: SAPS < Sequence Statistics < EMBL-EBI. EMBL-EBI. www.ebi.ac.uk. en. 2018-04-30.
10. Kobe B, Deisenhofer J . The leucine-rich repeat: a versatile binding motif . Trends Biochem. Sci. . 19 . 10 . 415–21 . October 1994 . 7817399 . 0968-0004. 10.1016/0968-0004(94)90090-6 .
11. Enkhbayar P, Kamiya M, Osaki M, Matsumoto T, Matsushima N . Structural principles of leucine-rich repeat (LRR) proteins . Proteins . 54 . 3 . 394–403 . February 2004 . 14747988 . 1097-0134 . 10.1002/prot.10605 . 19951452 .
12. Rhoads AR, Friedberg F . Sequence motifs for calmodulin recognition . FASEB J. . 11 . 5 . 331–40 . April 1997 . 9141499 . 0892-6638. 10.1096/fasebj.11.5.9141499 . free . 1877645 .
13. Rost B . Review: protein secondary structure prediction continues to rise . J. Struct. Biol. . 134 . 2–3 . 204–18 . 2001 . 11551180 . 1047-8477. 10.1006/jsbi.2001.4336 . 10.1.1.8.8169 .
14. Ouali M, King RD . Cascaded multiple classifiers for secondary structure prediction . Protein Sci. . 9 . 6 . 1162–76 . June 2000 . 10892809 . 2144653 . 0961-8368 . 10.1110/ps.9.6.1162 .
15. Cuff JA, Barton GJ . Application of multiple sequence alignment profiles to improve protein secondary structure prediction . Proteins . 40 . 3 . 502–11 . August 2000 . 10861942 . 0887-3585 . 10.1002/1097-0134(20000815)40:3<502::AID-PROT170>3.0.CO;2-Q . 855816 .
16. Jones DT . Protein secondary structure prediction based on position-specific scoring matrices . J. Mol. Biol. . 292 . 2 . 195–202 . September 1999 . 10493868 . 0022-2836. 10.1006/jmbi.1999.3091 . 15506630 .
17. Pagni M, Ioannidis V, Cerutti L, Zahn-Zabal M, Jongeneel CV, Falquet L . MyHits: a new interactive resource for protein annotation and domain identification . Nucleic Acids Res. . 32 . Web Server issue . W332–5 . July 2004 . 15215405 . 441617 . 0305-1048. 10.1093/nar/gkh479 .
18. de Castro E, Sigrist CJ, Gattiker A, Bulliard V, Langendijk-Genevaux PS, Gasteiger E, Bairoch A, Hulo N . ScanProsite: detection of PROSITE signature matches and ProRule-associated functional and structural residues in proteins . Nucleic Acids Res. . 34 . Web Server issue . W362–5 . July 2006 . 16845026 . 1362-4962. 1538847 . 10.1093/nar/gkl124 .
19. Web site: Results - mentha: the interactome browser. mentha.uniroma2.it. 2018-04-30.
20. Web site: LRRIQ3 - Leucine-rich repeat and IQ domain-containing protein 3 - Homo sapiens (Human) - LRRIQ3 gene & protein. www.uniprot.org. en. 2018-04-30.
21. Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML . Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage . Immunity . 15 . 4 . 603–15 . October 2001 . 11672542 . 1074-7613 . 10.1016/s1074-7613(01)00208-4. free .
22. Downes GB, Gautam N . The G protein subunit gene families . Genomics . 62 . 3 . 544–52 . December 1999 . 10644457 . 0888-7543. 10.1006/geno.1999.5992.
23. Tu Y, Li F, Wu C . Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways . Mol. Biol. Cell . 9 . 12 . 3367–82 . December 1998 . 9843575 . 25640 . 1059-1524 . 10.1091/mbc.9.12.3367 .
24. Era T . Bcr-Abl is a "molecular switch" for the decision for growth and differentiation in hematopoietic stem cells . Int. J. Hematol. . 76 . 1 . 35–43 . July 2002 . 12138893 . 10.1007/BF02982716 . 10269867 .
25. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ . Basic local alignment search tool . J. Mol. Biol. . 215 . 3 . 403–10 . October 1990 . 2231712 . 0022-2836. 10.1016/S0022-2836(05)80360-2 . 14441902 .
26. Web site: TimeTree :: The Timescale of Life. www.timetree.org. 2018-05-06.
27. Web site: Tissue expression of LRRIQ3 - Summary - The Human Protein Atlas. www.proteinatlas.org. 2018-05-06.
28. Web site: Search results < Expression Atlas < EMBL-EBI. github.com/gxa/atlas/graphs/contributors. EMBL-EBI Expression Atlas development team. www.ebi.ac.uk. en. 2018-04-30.
29. Web site: Experiment < Expression Atlas < EMBL-EBI. github.com/gxa/atlas/graphs/contributors. EMBL-EBI Expression Atlas development team. www.ebi.ac.uk. en. 2018-05-06.