User:Alfat003/sandbox

= SMIM5 =

Introduction
The human SMIM5 gene, located on chromosome 17, encodes the small integral membrane 5 protein. SMIM5 is also known as PP12104 and C17orf109. SMIM5 is an integral membrane protein localized in vesicles and the Golgi apparatus, and has a single transmembrane domain. Differential regulation of SMIM5 may be implicated in clear cell renal cell carcinoma pathology.

Gene Expression
In humans, SMIM5 is highly expressed in the kidney, esophagus, thyroid and small intestine. During embryonic development, the mRNA sequence is highly expressed in the glycinergic amacrine cells of the retina.

mRNA
There are nine transcript variants of SMIM5 in humans, and only one is protein-coding. Other variants are classified as non-coding due to the presence of an upstream open reading frame that is predicted to interfere with translation of the longest ORF. This makes them a candidate for nonsense-mediated mRNA decay (NMD).

General Protein Characteristics
The human SMIM5 protein is an integral, single-pass membrane protein. The functional protein is 77 amino acids in length.

Based on the Statistical Analysis of Protein Sequence tool, the molecular weight of the SMIM5 protein is 8.5 kDa. The isoelectric point is 7.16. There is one transmembrane sequence between amino acids 32 and 52, and no charge clusters.

The di-arginine motif may play a role in directing the integral membrane protein to/from the endoplasmic reticulum. The protein contains a domain of unknown function, DUF4713, between residues 8 - 52. This may be a region of interest because of its high level of conservation across orthologs.

Post-Translational Modifications
SMIM5 does not contain any significant predicted post-translational modifications, such as phosphorylation, N-glycosylation, sumoylation, or myristoylation.

Secondary Structure
SMIM5 contains several alpha-helix domains towards the N-terminus, and beta-pleated sheets towards the center of the sequence.

Interacting Proteins
Based on yeast two hybrid screens, the following proteins interact with SMIM5:

•RBFA (ribosome binding factor A): assists in the late maturation stage of the functional core of the 30s subunit of the ribosome

•EHHADH (enoyl-coA hydratase and 3-hydroxyacyl coA dehydrogenase): encodes an enzyme involved in peroxisomal oxidation of fatty acids and is expressed in the proximal renal tubule

•Znf391 (zinc finger protein 391): Belongs to the Krueppel C2H2-type zinc-finger protein family, contains 9 C2H2-type zinc fingers. A transcription factor binding site was located on the SMIM5 promoter sequence for a Krueppel C2H2 zinc-finger transcription factor

•PRTT2 (proline-rich transmembrane protein 2): involved in signaling in the brain, where SMIM5 is expressed at a low level

Regulation of Expression
Among the transcription factors with binding sites in the SMIM5 promoter sequence appear to be FOX genes and zinc finger transcription fingers. Within the zinc finger DNA-binding protein family are Kruppel-like factors, which also contain binding sites in the SMIM5 promoter sequence. Specifically, the MOK2 factor acts to repress transcription.

The Kaiso transcription factor recruits the N-CoR repressor complex to promote histone deacetylation and the formation of repressive chromatin structures in target gene promoters, and may contribute to the repression of target genes of the Wnt signaling pathway.

Homology
The SMIM5 gene is highly conserved in mammals, including the chimpanzee, Rhesus monkey, dog, cow, and mouse. It is also conserved in reptiles and birds, but not in bacteria or fungi. Based on a global sequence alignment of the human and mouse SMIM5 precursor proteins, the SMIM5 protein in the human is 76.9% identical to its ortholog in the mouse.

The domain of unknown function in the gene sequence (DUF4713) is among the most highly conserved regions. Based on a multiple sequence alignment of the human SMIM5 protein and its close orthologs, a sequence of two cysteine residues in the protein is completely conserved across all orthologs. One of the most distant orthologs is the Burmese python, which diverged from Homo sapiens approximately 312 million years ago.

Table 1: List of various orthologous species containing SMIM5 gene with reference to Homo sapiens sequence

Clinical Significance
According to a 2014 study that widely analyzed gene expression data in clear cell renal cell carcinoma (ccRcc), downregulation of SMIM5 may be implicated in ccRcc pathology. Among all the genes found to be downregulated in this disease, a general trend appears to be that their function is tied to biological pathways related to tissue remodeling and wound repair, blood clotting, vasodilatation, and energy metabolism.