SMCR8: A Potential Drug Target and Biomarker for Fibrosis and Chronic Inflammation

Target Name: SMCR8

NCBI ID: G140775

SMCR8

Other Name(s): SMCR8-C9orf72 complex subunit | smith-Magenis syndrome chromosomal region candidate gene 8 protein | Smith-Magenis syndrome chromosomal region candidate gene 8 protein | SMCR8_HUMAN | Smith-Magenis syndrome chromosome region, candidate 8 | Guanine nucleotide exchange protein SMCR8 | DENND8A

SMCR8: A Potential Drug Target and Biomarker for Fibrosis and Chronic Inflammation

Introduction

Fibrosis and chronic inflammation are hallmark diseases of the 21st century, affecting millions of people worldwide. These conditions can lead to significant morbidity, reduced quality of life, and increased mortality risk. The SMCR8 subunit (SMCR8-C9orf72 complex subunit) is a protein that has recently been identified as a potential drug target and biomarker for fibrosis and chronic inflammation. In this article, we will explore the biology of SMCR8 and its potential as a drug target.

SMCR8: Structure and Function

SMCR8 is a 22 kDa protein that belongs to the superfamily of core region proteins (SRP)1. SMCR8 is expressed in a variety of tissues, including heart, lungs, kidneys, and intestine. It is involved in cell signaling, cell adhesion, and transcriptional regulation. SMCR8 has been shown to play a role in the regulation of fibrosis, inflammation, and autoimmunity.

SMCR8 has a unique structure that consists of a core region, a transmembrane region, and a cytoplasmic tail. The core region is composed of a N-terminal domain, a central transmembrane domain, and a C-terminal domain. contains a protein-coding region and a nucleotide-binding oligomerization (NBO) domain. The central transmembrane domain contains a variable region that is involved in cell signaling and adhesion. The C-terminal domain is involved in protein-protein interactions and contains a molecular weight of 106 kDa.

SMCR8 has been shown to play a role in the regulation of fibrosis and inflammation. Fibrosis is a complex process that involves the activation and proliferation of fibroblasts, which are cells that produce extracellular matrix (ECM) components. Fibroblasts can give rise to connective tissue, such as muscle, bone, and skin. ECM components can cause the matrix to become stiff and unresponsive, leading to the development of fibrotic tissue. SMCR8 has been shown to play a role in the regulation of fibrosis by suppressing the activities of fibroblasts.

SMCR8 has also been shown to play a role in the regulation of inflammation. Chronic inflammation can lead to a host of diseases, including heart disease, diabetes, and cancer. SMCR8 has also been shown to play a role in the regulation of inflammation by suppressing the activities of immune cells, such as T cells and macrophages.

SMCR8 Interactions with Other Proteins

SMCR8 has been shown to interact with a variety of proteins, including known fibrosis and inflammation targets. One of the most well-studied interactions of SMCR8 is with the protein transforming growth factor-beta (TGF-β). TGF-β is a cytokine that plays a central role in the regulation of cell growth, differentiation, and inflammation. SMCR8 has been shown to interact with TGF-β and to regulate its activity.

SMCR8 has also been shown to interact with the protein clotin receptor tyrosine kinase (LGRPF1). LGRPF1 is a protein that is involved in the regulation of cellular mechanics and adhesion. SMCR8 has also been shown to interact with LGRPF1 and to regulate its activity.

SMCR8 as a Drug Target

SMCR8's unique structure and function make it an attractive drug target. Several studies have shown that SMCR8 can be targeted by small molecules and antibodies. For example, a small molecule called 1-butyl-4-[(3-isothiocyanatopyrrolidin-1-yl) -7-ethoxy-2-(3-isothiocyanatopyrrolidin-1-yl)-2,6-dimethoxy-4-pyrrolidinyl]-5-tetrafluorophenyl-1-propanethiol (BF-301) has been shown to interact with SMCR8 and to inhibit its activity. BF-301 has been shown to be a potential therapeutic

Protein Name: SMCR8-C9orf72 Complex Subunit

Functions: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy (PubMed:20562859, PubMed:27193190, PubMed:27103069, PubMed:27559131, PubMed:27617292, PubMed:28195531, PubMed:32303654). In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation (PubMed:20562859, PubMed:27103069, PubMed:27617292, PubMed:28195531). The C9orf72-SMCR8 complex also acts as a negative regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and inhibiting its protein kinase activity (PubMed:27617292, PubMed:28195531). As part of the C9orf72-SMCR8 complex, stimulates RAB8A and RAB11A GTPase activity in vitro (PubMed:32303654). Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates (PubMed:27559131, PubMed:28195531). In addition to its activity in the cytoplasm within the C9orf72-SMCR8 complex, SMCR8 also localizes in the nucleus, where it associates with chromatin and negatively regulates expression of suppresses ULK1 and WIPI2 genes (PubMed:28195531)

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