# CPE

## Overview
Carboxypeptidase E (CPE) is a gene that encodes the enzyme carboxypeptidase E, a metallocarboxypeptidase involved in the processing and sorting of prohormones and neuropeptides. This enzyme plays a critical role in the regulated secretory pathway, particularly within the trans-Golgi network, where it functions as a sorting receptor and facilitates the conversion of peptide precursors into their active forms by cleaving C-terminal basic residues (Ji2017Dissecting). CPE is characterized by its zinc-binding motif, which is essential for its catalytic activity, and exists in both membrane-bound and soluble forms due to post-translational modifications (Jung1991Structural; Manser1990Human). Beyond its enzymatic functions, CPE is involved in vesicle transport and interacts with various proteins, influencing processes such as neurotransmitter release and Wnt signaling (Ji2017Dissecting; Skalka2016Carboxypeptidase). Mutations in the CPE gene have been linked to several diseases, including diabetes, obesity, and neurodegenerative disorders, highlighting its clinical significance (Cawley2012New; Cong2017A).

## Structure
Carboxypeptidase E (CPE) is a protein involved in the processing of prohormones, characterized by its complex molecular structure. The primary structure of CPE consists of a polypeptide chain that includes a catalytic domain essential for its enzymatic activity (Ji2017Dissecting). The secondary structure features an amphiphilic alpha-helix at the COOH-terminal region, which is crucial for its pH-dependent membrane association. This helix has hydrophobic residues on one face and charged groups on the other, facilitating reversible binding to membranes (Fricker1990Identification).

The tertiary structure of CPE forms a globular shape, which is typical for proteins involved in enzymatic functions. CPE also contains a zinc-binding motif, which is a common feature in metallocarboxypeptidases, contributing to its catalytic activity (Jung1991Structural). The quaternary structure involves dimerization, which may be important for its function in prohormone processing (Ji2017Dissecting).

Post-translational modifications of CPE include glycosylation, which may affect its stability and activity (Manser1990Human). The protein exists in both membrane-bound and soluble forms, derived from a single mRNA species through post-translational processing (Manser1990Human). These structural features enable CPE to function effectively in the sorting and processing of prohormones within the trans-Golgi network.

## Function
Carboxypeptidase E (CPE) is a multifunctional protein involved in several critical cellular processes. In healthy human cells, CPE primarily functions in the processing and sorting of prohormones and neuropeptides within the regulated secretory pathway. It acts as a sorting receptor at the trans-Golgi network (TGN), directing prohormones such as proinsulin and proenkephalin to dense core secretory granules for regulated secretion (Ji2017Dissecting). CPE is most active in acidic environments like the TGN and secretory granules, where it cleaves C-terminal basic residues from peptide precursors, facilitating their conversion into active forms (Ji2017Dissecting).

CPE also plays a role in vesicle transport, interacting with microtubule proteins to facilitate the anterograde and retrograde transport of vesicles, such as those containing brain-derived neurotrophic factor (BDNF) in neurons (Ji2017Dissecting). The protein's cytoplasmic tail interacts with dynactin, recruiting kinesins and dynein for vesicle transport, which is crucial for maintaining vesicle homeostasis and secretion (Ji2017Dissecting).

CPE's activity is regulated by pH and calcium ion levels, with zinc being essential for its catalytic function (Ji2017Dissecting). It is also involved in the modulation of metabolic and glucose homeostasis, bone remodeling, and neuroprotection (Cawley2012New).

## Clinical Significance
Mutations and alterations in the carboxypeptidase E (CPE) gene are associated with several diseases and conditions. In cancer, particularly neuroendocrine tumors, CPE and its variant CPE-ΔN serve as diagnostic and prognostic biomarkers. Elevated CPE expression is linked to a good prognosis in pulmonary neuroendocrine tumors, while high CPE-ΔN mRNA levels correlate with poor prognosis in pheochromocytomas/paragangliomas (PHEO/PGL) and metastatic disease in hepatocellular carcinoma and colorectal cancer (Cawley2012New).

In the context of diabetes, mutations in the CPE gene can lead to hyperproinsulinemia and type 2 diabetes mellitus (T2DM). A specific single nucleotide polymorphism (SNP), rs34516004, results in an enzymatically inactive mutant associated with a higher risk of diabetes (Cawley2012New). CPE mutations have also been linked to obesity and diabetes in mouse models, with similar phenotypes observed in humans (Sabiha2021In).

CPE gene alterations are implicated in neurodegenerative diseases. A mutation resulting in a tryptophan to arginine substitution (W235R) in the CPE protein is associated with a loss of neuroprotective function, contributing to neurodegeneration (Cong2017A). Additionally, CPE mutations have been linked to increased severity of coronary atherosclerosis (Jia2007Association).

## Interactions
Carboxypeptidase E (CPE) interacts with various proteins, playing a crucial role in cellular processes. CPE functions as a sorting receptor in the regulated secretory pathway (RSP) by binding to prohormones such as pro-opiomelanocortin (POMC), proinsulin, and proenkephalin at the trans-Golgi network (TGN). This interaction is essential for the correct sorting and packaging of these proteins into secretory granules for regulated release (Ji2017Dissecting; Cool1997Carboxypeptidase).

CPE also interacts with the Wnt3a protein, inhibiting its secretion and activity. The N-terminal domain of CPE facilitates the aggregation and sedimentation of Wnt3a, reducing its levels and signaling ability. This interaction suggests a mechanism for downregulating the Wnt signaling pathway (Skalka2016Carboxypeptidase).

In neurons, CPE is involved in synaptic vesicle localization and neurotransmitter secretion. It interacts with cytoplasmic proteins to retain synaptic vesicles close to the presynaptic membrane, which is crucial for neurotransmitter release (Cawley2012New). CPE's cytoplasmic tail interacts with motor proteins such as kinesin and dynein, facilitating vesicle transport (Ji2017Dissecting; Cawley2012New).


## References


[1. (Ji2017Dissecting) Lin Ji, Huan-Tong Wu, Xiao-Yan Qin, and Rongfeng Lan. Dissecting carboxypeptidase e: properties, functions and pathophysiological roles in disease. Endocrine Connections, 6(4):R18–R38, May 2017. URL: http://dx.doi.org/10.1530/ec-17-0020, doi:10.1530/ec-17-0020. This article has 68 citations and is from a peer-reviewed journal.](https://doi.org/10.1530/ec-17-0020)

[2. (Fricker1990Identification) L D Fricker, B Das, and R H Angeletti. Identification of the ph-dependent membrane anchor of carboxypeptidase e (ec 3.4.17.10). Journal of Biological Chemistry, 265(5):2476–2482, February 1990. URL: http://dx.doi.org/10.1016/s0021-9258(19)39824-2, doi:10.1016/s0021-9258(19)39824-2. This article has 129 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0021-9258(19)39824-2)

[3. (Jung1991Structural) Yong-Keun Jung, Cheryl J. Kunczt, Randy K. Pearson, Jack E. Dixon, and Lloyd D. Fricker. Structural characterization of the rat carboxypeptidase-e gene. Molecular Endocrinology, 5(9):1257–1268, September 1991. URL: http://dx.doi.org/10.1210/MEND-5-9-1257, doi:10.1210/mend-5-9-1257. This article has 57 citations.](https://doi.org/10.1210/MEND-5-9-1257)

[4. (Cong2017A) Lin Cong, Yong Cheng, Niamh X. Cawley, Saravana R. K. Murthy, and Y. Peng Loh. A novel single nucleotide t980c polymorphism in the human carboxypeptidase e gene results in loss of neuroprotective function. PLOS ONE, 12(1):e0170169, January 2017. URL: http://dx.doi.org/10.1371/journal.pone.0170169, doi:10.1371/journal.pone.0170169. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0170169)

[5. (Manser1990Human) E Manser, D Fernandez, L Loo, P Y Goh, C Monfries, C Hall, and L Lim. Human carboxypeptidase e. isolation and characterization of the cdna, sequence conservation, expression and processing in vitro. Biochemical Journal, 267(2):517–525, April 1990. URL: http://dx.doi.org/10.1042/bj2670517, doi:10.1042/bj2670517. This article has 50 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj2670517)

[6. (Skalka2016Carboxypeptidase) N Skalka, M Caspi, L Lahav-Ariel, Y P Loh, K Hirschberg, and R Rosin-Arbesfeld. Carboxypeptidase e (cpe) inhibits the secretion and activity of wnt3a. Oncogene, 35(50):6416–6428, July 2016. URL: http://dx.doi.org/10.1038/onc.2016.173, doi:10.1038/onc.2016.173. This article has 10 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/onc.2016.173)

[7. (Sabiha2021In) Bibi Sabiha, Attya Bhatti, Sohaib Roomi, Peter John, and Johar Ali. In silico analysis of non-synonymous missense snps (nssnps) in cpe, gnas genes and experimental validation in type ii diabetes mellitus through next generation sequencing. Genomics, 113(4):2426–2440, July 2021. URL: http://dx.doi.org/10.1016/j.ygeno.2021.05.022, doi:10.1016/j.ygeno.2021.05.022. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ygeno.2021.05.022)

[8. (Jia2007Association) En-Zhi Jia, Jie Wang, Zhi-Jian Yang, Tie-Bing Zhu, Lian-Sheng Wang, Hui Wang, Chun-Jian Li, BO Chen, Ke-Jiang Cao, Jun Huang, and Wen-Zhu Ma. Association of the mutation for the human carboxypeptidase e gene exon 4 with the severity of coronary artery atherosclerosis. Molecular Biology Reports, 36(2):245–254, December 2007. URL: http://dx.doi.org/10.1007/s11033-007-9173-4, doi:10.1007/s11033-007-9173-4. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s11033-007-9173-4)

[9. (Cool1997Carboxypeptidase) David R Cool, Emmanuel Normant, Fu-sheng Shen, Hao-Chia Chen, Lewis Pannell, Ying Zhang, and Y.Peng Loh. Carboxypeptidase e is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in cpefat mice. Cell, 88(1):73–83, January 1997. URL: http://dx.doi.org/10.1016/s0092-8674(00)81860-7, doi:10.1016/s0092-8674(00)81860-7. This article has 347 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s0092-8674(00)81860-7)

[10. (Cawley2012New) Niamh X. Cawley, William C. Wetsel, Saravana R. K. Murthy, Joshua J. Park, Karel Pacak, and Y. Peng Loh. New roles of carboxypeptidase e in endocrine and neural function and cancer. Endocrine Reviews, 33(2):216–253, March 2012. URL: http://dx.doi.org/10.1210/er.2011-1039, doi:10.1210/er.2011-1039. This article has 86 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1210/er.2011-1039)