XK-related protein 4 (XKR4)

XK-related protein 4 (XKR4) is a member of the X-Kell related (Xkr) protein family and functions as a **phospholipid scramblase** that catalyzes the bidirectional movement (“scrambling”) of phosphatidylserine across the plasma membrane, a process critical for the recognition and clearance of apoptotic cells. Activation involves structural changes—often mediated by caspase cleavage, dimerization, binding of the XRCC4 protein fragment, and crucially, extracellular calcium coordination between transmembrane helices—which exposes phosphatidylserine as an “eat me” signal[1]. However, recent research demonstrates that purified, full-length human XKR4 functions as a monomeric scramblase without absolute dependence on caspase processing or oligomerization, suggesting intrinsic scrambling activity[2][3]. The protein consists of ten transmembrane helices and contains an electronegative vestibule thought to induce membrane thinning, facilitating lipid translocation. Defective XKR4 function impairs dead cell clearance, leading to inflammation; however, no direct pharmacological modulators or disease-targeted therapies have been reported. XKR4 is structurally and mechanistically related to XKR8 and XKR9, but remains distinct in its regulatory requirements and monomeric activity[1][2].

Other names

KIAA1889XRG4hXKR4XK-related protein 4, processed formXK Kell blood group precursor-related family, member 4X-linked Kx blood group related 4Kell blood group complex subunit-related family, member 4

Not applicable (no drugs directly targeting XKR4 documented)