Signal-Regulatory Protein

Signal-Regulatory Protein

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About SIRP / Signal-Regulatory Protein:

Signal regulatory proteins (SIRPs; also known as myeloid-paired receptors) are membrane proteins produced by leukocytes that regulate immune cells to provide an effective immune response to invaders while minimizing self-harm. They are called CD proteins (cluster of differentiation). SIRP family members' extracellular regions share substantial similarity but have distinct signaling potentials, with each family member mediating either an activating or inhibitory signal. SIRPA (SIRP; CD172a), SIRPB1 (SIRP; CD172b), SIRPB2, SIRPD, and SIRPG (SIRP; CD172g) are the five SIRP genes discovered in humans.

SIRP Structure
Signal regulatory protein (SIRP) is a membrane receptor that activates CD47 to provide inhibitory signals to myeloid cells. The N-terminal ligand binding domain has a unique immunoglobulin superfamily V-like fold, as shown by the high-resolution x-ray structure. CD47 seems to be bound at a surface including the BC, FG, and DE loops, which separates it from other immunoglobulin superfamily surface proteins that employ the faces of the fold yet resemble antigen receptors.

Signal-Regulatory Protein Interactions
The SIRP interaction is restricted to a single domain, and its usage of an extended DE loop adds to the resemblance with T cell receptor binding and suggests that they are evolutionarily related. The use of loops to construct the CD47-binding surface provides a method for minor sequence alterations to modify binding specificity, explaining why SIRP family members have varied binding characteristics.

SIRP Function
SIRPs work with other proteins to exert regulatory effects. One well-known relationship is that between the inhibitory SIRP protein and CD47, which functions as an immuno checkpoint. SIRP/CD47 blockade is being used as an immuno-oncology approach, with either SIRP or CD47 being inhibited. Because of their structural similarities and the fact that each gene is polymorphic, creating monoclonal antibodies that are selective for particular SIRPs is difficult.