# BMPR2

## Overview
The BMPR2 gene encodes the bone morphogenetic protein receptor type 2, a critical component of the transforming growth factor-beta (TGF-β) superfamily signaling pathways. This gene is located on chromosome 2q33-q34 and is responsible for producing a serine/threonine kinase receptor that plays a pivotal role in cellular processes such as growth, differentiation, and apoptosis. The BMPR2 protein is a transmembrane receptor that consists of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular kinase domain, which is essential for its signaling function (Liu1995Human; Mace2006High). The receptor primarily interacts with type I BMP receptors to mediate the effects of bone morphogenetic proteins, influencing various physiological and pathological processes, including vascular homeostasis and pulmonary arterial hypertension (Machado2006Mutations; Hiepen2019BMPR2). Mutations in the BMPR2 gene are notably associated with several diseases, underscoring its significance in maintaining normal cellular function and integrity (Kim2017Clinical).

## Structure
The BMPR2 protein is a serine/threonine kinase receptor involved in the BMP signaling pathway. It consists of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular kinase domain. The extracellular domain (ECD) of BMPR2 features a three-finger toxin fold, which is common among TGF-beta family receptors. This fold is characterized by eight conserved cysteine residues forming four disulfide bonds, with an additional disulfide bridge between Cys99 and Cys116 (Mace2006High). The ECD also includes a unique disulfide bridge between Cys94 and Cys117, which is important for ligand binding (Mace2006High).

The kinase domain of BMPR2 exhibits a typical bilobal architecture, with specific insertions that define the BMP/TGF-beta receptor family, such as the L45 loop and E6 loop. The kinase domain adopts an active conformation, characterized by a closed conformation of the N and C-terminal lobes and a salt bridge between catalytic residues Lys230 and Glu243 (Chaikuad2019Structural). The quaternary structure involves the formation of heterodimeric complexes with type I receptors, such as ALK2, which is crucial for receptor signaling (Agnew2021Structural). Common post-translational modifications include phosphorylation, which is essential for its signaling function (Agnew2021Structural).

## Function
The BMPR2 gene encodes the bone morphogenetic protein receptor type 2, a serine/threonine kinase receptor that is integral to the BMP signaling pathway. In healthy human cells, BMPR2 is primarily active in the cell membrane, where it forms complexes with type 1 receptors such as ALK1, ALK2, ALK3, or ALK6. This complex formation is crucial for the activation of SMAD transcription factors, which regulate various cellular processes, including endothelial cell function and vascular homeostasis (Hiepen2019BMPR2).

BMPR2 plays a protective role in endothelial cells by modulating the balance between BMP and TGFβ signaling pathways. It acts as a gatekeeper, preventing excessive TGFβ responses that can lead to endothelial dysfunction. This function is essential for maintaining the structural integrity of the cellular environment and preventing pathological changes such as endothelial-to-mesenchymal transition (EndMT) (Hiepen2019BMPR2).

In pulmonary arterial endothelial cells, BMPR2 signaling promotes cell survival by reducing apoptosis, particularly under stress conditions such as serum deprivation and TNF-α exposure. This protective effect is mediated through ligands like BMP-2 and BMP-7, highlighting BMPR2's role in maintaining endothelial cell viability and preventing pulmonary hypertension (Teichert-Kuliszewska2006Bone).

## Clinical Significance
Mutations in the BMPR2 gene are significantly associated with pulmonary arterial hypertension (PAH), a progressive vascular disorder characterized by elevated pulmonary artery pressure due to the narrowing of precapillary pulmonary arteries. These mutations are found in a substantial proportion of familial PAH cases and a notable percentage of idiopathic cases, indicating a strong genetic predisposition (Machado2006Mutations; Sztrymf2008Clinical). The mutations often result in nonsense, frameshift, and splice-site defects, leading to premature transcript termination and likely loss through nonsense-mediated decay, contributing to haploinsufficiency (Machado2006Mutations; Austin2009Truncating).

BMPR2 mutations are also linked to familial primary pulmonary hypertension (FPPH), where they disrupt normal receptor function, crucial for maintaining blood vessel integrity (Lane2000Heterozygous). In sporadic primary pulmonary hypertension (PPH), germline mutations in BMPR2 are present in a significant portion of patients, suggesting a genetic basis similar to familial cases (Thomson2000Sporadic).

Beyond PAH, BMPR2 mutations are implicated in other conditions such as hereditary hemorrhagic telangiectasia (HHT), chronic obstructive pulmonary disease (COPD), and certain cancers, including prostatic neoplasms and colorectal cancer (Kim2017Clinical). These mutations can disrupt BMP signaling pathways, leading to various phenotypic abnormalities and contributing to the pathogenesis of these diseases (Kim2017Clinical).

## Interactions
BMPR2 (bone morphogenetic protein receptor type 2) is a key component in the BMP signaling pathway, interacting with various proteins to mediate cellular responses. BMPR2 forms complexes with type I BMP receptors, such as BMPR-IA, BMPR-IB, and ActR-I, to bind BMP ligands like BMP-2 and BMP-7. This interaction is ligand-dependent and essential for effective signal transduction (Liu1995Human). The kinase activity of both type I and type II receptors, including BMPR2, is crucial for signaling (Liu1995Human).

BMPR2 also interacts with ALK2, forming heterodimers and tetramers that are important for BMP4-mediated SMAD signaling. The interaction involves the C-lobe and N-lobe interfaces of the kinase domains, with specific mutations affecting the stability and function of these complexes (Agnew2021Structural). The N-glycosylation of BMPR2 enhances its ability to bind BMP2, highlighting the importance of post-translational modifications in its function (Lowery2013N-linked).

BMPR2 does not participate in TGF-β or activin receptor signaling, as it does not bind these ligands or form complexes with their receptors in mammalian cells (Liu1995Human). However, it can interact with ALK4 in activin signaling, influencing Fshb transcription in certain cellular contexts (Rejon2013Activins).


## References


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