REEP5

REEP5 is located on chromosome 5 between base pairs 112876385 to 112922289 on the minus strand.[8] The gene includes five exons.[8] The genes DCP2 and SRP19 are located upstream and downstream of REEP5 in humans.[9]

The protein is a member of the REEP family, which generally facilitate intracellular trafficking through alterations to the endoplasmic reticulum, and which have the ability to enhance activity of G-protein coupled receptors.[10] The human protein is 189 amino acids in length, containing two transmembrane regions and one named region- TB2_DP1_HVA22,[11] The pre-modification protein mass is 21.5 kdal.[12] Compared to the SwissProt collection of human proteins, REEP5 is composed of normal percentages of all amino acids.[12] Aside from a long stretch of electrically neutral amino acids, no significant patterns appear.[12] A second isoform exists in humans, and is 131 amino acids in length as the result of a change after the 117th amino acid.[13] Most of the fifth exon is not included.

Protein Topology of the Human REEP5 protein as predicted by PROTTER

REEP5 interacts with a number of proteins, including Regulator of G Protein signalling 2, which was detected using Yeast 2 Hybridization. RGS2 plays a role in G protein signalling 2 pathways and the contraction of smooth muscle tissues. Derlin 2 (Derl2) interacts with REEP5 as detected by anti-tag coimmunoprecipation and degrades misfolded glycoproteins in the endoplasmic reticulum.[26] Cholinergic Receptor Muscarinic 5 was detected as an interactant by ubiquitin reconstruction.[27] CHRM5 binds acetylcholine, and can impact the function of the central and peripheral nervous systems.[28]

Regulator of G Protein Signaling 2 was also detected with Yeast 2 Hybridization and is a regulator of G-protein receptor which may be involved with the contraction of smooth vascular muscle.[27][29]

Four proteins were experimentally detected across several papers.[30] Three of them, Atlastin GTPase 1, Atlastin GTPase 2, and Zinc Finger FYVE-Type Containing 27 are related to the structuring of the endoplasmic reticulum (tubules in particular), the development of axons, or neuron growth.[17][31] The fourth is REEP6, which is responsible for transporting receptors to the cell surface, as well as regulating endoplasmic reticulum structure.[32]

Research has linked REEP5 to several diseases and disorders.

In colon cancer, expression of REEP5 enhances activity of CXCR1, a protein receptor which contributes to the growth and spread of cancer cells. Researchers have found that under expression of REEP5 reduces the efficiency of CXRC1, and reduces the ability of lung cancer cells to metastasize.[10] This provides both a potential target for cancer therapy and further evidence of REEP5 having function as a protein which increases activity of other receptor proteins. Another type of cancer related to REEP5 is colon cancer, in which the protein normally interacts with and neutralizes HCCR1, a protein which would otherwise interfere with P53 and contribute to the progression of cancer.[34]

REEP5 has also been linked to heart disorders, and research into the connection has revealed that it helps organize the junctional Sarcoplasmic Reticulum in myocytes. REEP5 aligns the junctional SR to T-tubules, which promotes effective release of Calcium ions. When protein function is disrupted the junction becomes misaligned and Calcium ion release becomes less effective. Given the importance of Calcium ions to the muscle contractions which power the heart, targeting REEP5 has the potential to be a therapeutic option in some disorders.[35]

Additionally, there is some statistical evidence linking certain SNPs found within REEP5 mRNA to Major Depressive Disorder.[36] However, a biological mechanism has not been confirmed, and the study only looked at a limited population.[36]