# TMEM50A

## Overview
TMEM50A is a gene that encodes the transmembrane protein 50A, a member of the TMEM50 protein family characterized by its four transmembrane domains. This protein is primarily involved in the regulation of RH gene activity, particularly influencing the expression of the RHD and RHCE genes, which are essential for blood group antigen expression (Chen2021Preliminary). The transmembrane protein 50A is localized to the secretory pathway and is predicted to have a stable and compact structure, with a molecular weight of 17,400 Da and a basal isoelectric point of 5.57 (Srivastava2017Linear). TMEM50A's role extends to potential involvement in embryonic nervous system development and various clinical contexts, including its up-regulation in mucinous tumors of the ovary and underexpression in kidney cancer associated with von-Hippel Lindau disease (Wamunyokoli2006Expression; Beroukhim2009Patterns). Despite its regulatory functions, TMEM50A does not appear to affect ammonium transport in cells (Chen2021Preliminary).

## Structure
The TMEM50A protein is characterized by four transmembrane domains, which are crucial for its localization to the secretory pathway (Srivastava2017Linear). The primary structure of TMEM50A consists of 157 amino acid residues (Srivastava2017Linear). The protein has a molecular weight of 17,400 Da and a basal isoelectric point of 5.57, indicating its physicochemical properties (Srivastava2017Linear).

In terms of secondary structure, the protein's transmembrane domains likely form alpha helices, a common feature in membrane-spanning regions. The tertiary structure of TMEM50A has been modeled and refined, showing high stereochemical quality with 85.8% of residues in favored regions of the Ramachandran plot (Srivastava2017Linear). Molecular dynamic simulations suggest that TMEM50A has a compact and stable structure with low RMS fluctuations, indicating limited flexibility and stable dynamic behavior (Srivastava2017Linear).

Post-translational modifications of TMEM50A include two serine phosphorylation sites, one N-linked glycosylation site, and one tyrosine phosphorylation site, which may influence its function and interactions (Srivastava2017Linear). The protein is classified as stable, with an instability index of 28.66, an aliphatic index of 95.10, and a GRAVY score of 0.580, reflecting its hydrophobic character (Srivastava2017Linear).

## Function
TMEM50A, encoded by the SMP1 gene, is a transmembrane protein located in the intergenic region of the RH gene locus, specifically between the RHD and RHCE genes. It is part of the TMEM50 protein family and contains the UPF0220 Pfam domain (Attwood2016Topology). TMEM50A is involved in regulating RH gene activity, particularly influencing the expression of the RHD and RHCE genes. Overexpression of TMEM50A has been shown to significantly increase RHCE gene activity, while its inhibition decreases the expression of both RHCE and RHD (Chen2021Preliminary).

The protein is predicted to have four transmembrane domains, which may direct it to the secretory pathway. It is characterized by a molecular weight of 17,400 Da and a basal isoelectric point of 5.57, indicating its stability and compact structure (Srivastava2017Linear). TMEM50A may regulate RH gene expression by affecting mRNA stability through splicing activities, and it might also play a role in embryonic nervous system development (Chen2021Preliminary). Despite its influence on gene expression, TMEM50A overexpression does not affect the ammonium transport function of cells (Chen2021Preliminary).

## Clinical Significance
TMEM50A has been implicated in various clinical contexts due to its altered expression levels and potential interactions. In mucinous tumors of the ovary, TMEM50A is significantly up-regulated, with a mean fold change of 8.5 in mucinous adenocarcinoma compared to cystadenoma. This suggests a role in the clinicopathologic features of these tumors, possibly through pathways involving drug resistance, cell cycle regulation, and cytoskeletal modulation (Wamunyokoli2006Expression).

In the context of kidney cancer, TMEM50A is identified as an underexpressed gene in the deletion peak region of chromosome 1p in von-Hippel Lindau disease-associated and sporadic clear cell carcinoma. This underexpression may indicate its involvement in tumor suppression or progression (Beroukhim2009Patterns).

TMEM50A also plays a regulatory role in the expression of RH genes, specifically RHD and RHCE, which are crucial for blood group antigen expression. Alterations in TMEM50A expression can significantly impact RHCE gene activity, potentially affecting blood group phenotypes (Chen2021Preliminary).

While TMEM50A's direct link to specific diseases remains under investigation, its involvement in these pathways highlights its potential clinical significance in cancer and blood group regulation.


## References


[1. (Wamunyokoli2006Expression) Fred W. Wamunyokoli, Tomas Bonome, Ji-Young Lee, Colleen M. Feltmate, William R. Welch, Mike Radonovich, Cindy Pise-Masison, John Brady, Ke Hao, Ross S. Berkowitz, Samuel Mok, and Michael J. Birrer. Expression profiling of mucinous tumors of the ovary identifies genes of clinicopathologic importance. Clinical Cancer Research, 12(3):690–700, February 2006. URL: http://dx.doi.org/10.1158/1078-0432.CCR-05-1110, doi:10.1158/1078-0432.ccr-05-1110. This article has 81 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.CCR-05-1110)

[2. (Beroukhim2009Patterns) Rameen Beroukhim, Jean-Philippe Brunet, Arianna Di Napoli, Kirsten D. Mertz, Apryle Seeley, Maira M. Pires, David Linhart, Robert A. Worrell, Holger Moch, Mark A. Rubin, William R. Sellers, Matthew Meyerson, W. Marston Linehan, William G. Kaelin, and Sabina Signoretti. Patterns of gene expression and copy-number alterations in von-hippel lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Research, 69(11):4674–4681, June 2009. URL: http://dx.doi.org/10.1158/0008-5472.can-09-0146, doi:10.1158/0008-5472.can-09-0146. This article has 328 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/0008-5472.can-09-0146)

[3. (Chen2021Preliminary) Hongtian Chen, Piao Lv, Ziwei Liu, Wanjun Chen, Yuan Yao, Chixiang Liu, Qiong Cao, and Huayou Zhou. Preliminary study on the function of <scp>tmem50a</scp> and its correlation with the <scp>rh</scp> genes. Transfusion Medicine, 31(4):277–285, April 2021. URL: http://dx.doi.org/10.1111/tme.12778, doi:10.1111/tme.12778. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/tme.12778)

[4. (Attwood2016Topology) Misty M. Attwood, Arunkumar Krishnan, Valentina Pivotti, Samira Yazdi, Markus Sällman Almén, and Helgi B. Schiöth. Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4tms) in the human genome. BMC Genomics, March 2016. URL: http://dx.doi.org/10.1186/s12864-016-2592-7, doi:10.1186/s12864-016-2592-7. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12864-016-2592-7)

[5. (Srivastava2017Linear) Upasna Srivastava, Satendra Singh, Budhyash Gautam, Pramod Yadav, Madhu Yadav, George Thomas, and Gurmit Singh. Linear epitope prediction in hpv type 16 e7 antigen and their docked interaction with human tmem 50a structural model. Bioinformation, 13(05):122–130, May 2017. URL: http://dx.doi.org/10.6026/97320630013122, doi:10.6026/97320630013122. This article has 7 citations.](https://doi.org/10.6026/97320630013122)