KIRREL - kirre like nephrin family adhesion molecule | Elisa - Clia - Antibody - Protein

Background

KIRREL, also known as kin of IRRE-like protein or NEPH1, is part of the nephrin-like protein family, which plays a significant role in cell adhesion and signal transduction processes in various tissues. The gene encoding KIRREL is located on chromosome 1q23.1 in humans. KIRREL proteins are characterized by their involvement in the development and maintenance of the slit diaphragm in the kidney's glomerulus, a key structure in the filtration barrier. The importance of KIRREL in maintaining glomerular filtration function highlights its role in kidney health and disease.

Protein Structure

KIRREL is a type I transmembrane protein consisting of several distinct domains that contribute to its function:

1. Extracellular Domain: This region includes three immunoglobulin (Ig)-like domains that facilitate protein-protein interactions necessary for cell adhesion. These Ig-like domains are crucial for the formation and maintenance of the slit diaphragm between podocytes in the kidney.
2. Transmembrane Domain: A single transmembrane helix anchors the protein within the cell membrane, allowing it to act as a bridge between the extracellular environment and intracellular signaling pathways.
3. Intracellular Domain: The cytoplasmic tail of KIRREL contains several conserved motifs, including proline-rich regions and phosphorylation sites, which are involved in intracellular signaling cascades. These motifs enable interactions with cytosolic proteins, contributing to the activation of downstream signaling pathways that regulate cell behavior.

Classification and Subtypes

KIRREL belongs to the nephrin-like protein family, which includes several members with similar structures and functions. This family is part of the larger immunoglobulin superfamily (IgSF), known for its diverse roles in cell adhesion and immune response. Within the nephrin-like protein family, KIRREL can be classified alongside other members such as NEPH2 and NEPH3, each playing specific roles in various tissues.

1. KIRREL1 (NEPH1): The primary form, involved in kidney podocyte function.
2. KIRREL2 (NEPH2): Primarily expressed in the nervous system, contributing to synaptic function.
3. KIRREL3 (NEPH3): Also expressed in the nervous system, implicated in neural development and connectivity.

Function and Biological Significance

KIRREL proteins are crucial for maintaining the integrity of the slit diaphragm in kidney glomeruli, which is essential for the filtration of blood. The primary functions and biological significance of KIRREL include:

1. Cell Adhesion: KIRREL mediates homophilic and heterophilic interactions with other slit diaphragm proteins such as nephrin and podocin. These interactions are vital for the structural integrity of the slit diaphragm and effective filtration barrier function.
2. Signal Transduction: The cytoplasmic domain of KIRREL interacts with intracellular signaling molecules, including kinases and adaptor proteins, to transmit signals that regulate cell survival, proliferation, and differentiation. These signaling pathways are essential for podocyte health and function.
3. Nephron Development: During kidney development, KIRREL plays a role in the formation of the glomerular filtration barrier. It is involved in the differentiation and maintenance of podocytes, which are specialized cells critical for kidney function.
4. Neuronal Function: KIRREL proteins in the nervous system contribute to synapse formation and maintenance, affecting neural connectivity and communication.

Clinical Issues

Mutations or dysregulation of KIRREL can lead to severe clinical conditions, particularly related to kidney function:

1. Nephrotic Syndrome: Genetic mutations in KIRREL can cause congenital nephrotic syndrome, characterized by massive proteinuria, hypoalbuminemia, and edema. This condition underscores the importance of KIRREL in maintaining the glomerular filtration barrier.
2. Focal Segmental Glomerulosclerosis (FSGS): Alterations in KIRREL expression or function are associated with FSGS, a disease leading to scarring of the glomeruli and progressive kidney failure. Understanding KIRREL's role in this context is crucial for developing targeted therapies.
3. Kidney Disease Progression: Dysregulation of KIRREL signaling pathways can contribute to the progression of chronic kidney diseases, highlighting its potential as a biomarker and therapeutic target.
4. Neurological Disorders: Although primarily studied in the context of kidney function, KIRREL family proteins' roles in the nervous system suggest potential implications in neurological disorders, particularly those involving synaptic dysfunction.

Summary

KIRREL, or NEPH1, is a key protein in the nephrin-like family, integral to maintaining the filtration barrier in the kidney and playing roles in neural connectivity. Its structure includes extracellular Ig-like domains, a transmembrane segment, and an intracellular domain with signaling motifs, facilitating its functions in cell adhesion and signal transduction. Dysregulation of KIRREL is implicated in severe kidney disorders, such as nephrotic syndrome and FSGS, and potentially in neurological conditions. Understanding KIRREL's roles and mechanisms opens avenues for targeted therapies and improved clinical outcomes in kidney and neurological diseases.