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2.A.112 The KX Blood-group Antigen (KXA) Family

McLeod syndrome is an X-linked human disorder characterized by abnormalities in the neuromuscular and hematopoetic systems. The KX blood group antigen mRNA expression pattern correlates with the McLeod phenotype. The KX gene codes for a novel protein with characteristics of membrane transporters. The protein has been proposed to be a Na+ -dependent neutral amine and/or oligopeptide transporter. It is predicted to be 444 amino acyl residues in length and exhibits 10 putative TMSs (Ho et al. 1994). The protein has distant homologues in animals such as Ciona intestinalis (P91583; TC# 2.A.112.1.18). The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of the XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis (Peng et al. 2007). Several of these proteins are Phosphatidyl serine flippases (from the cytoplasmic side of the membrane to the external side).

Two covalently linked proteins, Kell and XK, constitute the Kell blood group system. Kell, a 93-Kd type II glycoprotein, is highly polymorphic and carries all but 1 of the known Kell antigens, and XK, which traverses the membrane 10 times, carries a single antigen, the ubiquitous Kx. The Kell/XK complex is not limited to erythroid tissues and may have multiple physiological roles. Absence of XK is associated with abnormal red cell morphology and late-onset forms of nerve and muscle abnormalities, whereas the other protein component, Kell, is an enzyme whose principal known function is the production of a potent bioactive peptide, ET-3 (Lee et al. 2000).

The X-linked McLeod syndrome is defined by absent Kx red blood cell antigen and weak expression of Kell antigens. Most carriers of this McLeod blood group phenotype have acanthocytosis and elevated serum creatine kinase levels and are prone to develop a severe neurological disorder resembling Huntington's disease. Onset of neurological symptoms ranges between 25 and 60 years, and the penetrance of the disorder appears to be high. Additional symptoms of the McLeod neuroacanthocytosis syndrome that warrant therapeutic and diagnostic considerations include generalized seizures, neuromuscular symptoms leading to weakness and atrophy, and cardiopathy mainly manifesting with atrial fibrillation, malignant arrhythmias and dilated cardiomyopathy (Jung et al. 2007)

A classic feature of apoptotic cells is the cell-surface exposure of phosphatidylserine (PtdSer) as an 'eat me' signal for engulfment. Suzuki et al. 2013 showed that the Xk-family protein Xkr8 mediates PtdSer exposure in response to apoptotic stimuli. Mouse Xkr8(-/-) cells or human cancer cells in which Xkr8 expression was repressed by hypermethylation failed to expose PtdSer during apoptosis and were inefficiently engulfed by phagocytes. Xkr8 was activated directly by caspases and required a caspase-3 cleavage site for its function. CED-8, the only Caenorhabditis elegans Xk-family homolog, also promoted apoptotic PtdSer exposure and cell-corpse engulfment. Thus, Xk-family proteins have evolutionarily conserved roles in promoting the phagocytosis of dying cells by altering the phospholipid distribution in the plasma membrane (Suzuki et al. 2013). 

During apoptosis, phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, is exposed on the surface of apoptotic cells and serves as an 'eat-me' signal to trigger phagocytosis (see previous paragraph). Chen et al. 2013 reported that CED-8, a Caenorhabditis elegans protein implicated in controlling the kinetics of apoptosis and a homologue of the XK family proteins, is a substrate of the CED-3 caspase. Cleavage of CED-8 by CED-3 activates its proapoptotic function and generates a carboxyl-terminal cleavage product, acCED-8, that promotes PS externalization in apoptotic cells and can induce ectopic PS exposure in living cells. Consistent with its role in promoting PS externalization in apoptotic cells, ced-8 is important for cell corpse engulfment in C. elegans. Thus, there is a link between caspase activation and PS externalization, which triggers phagocytosis of apoptotic cells.

The generalized reactions proposed to be catalyzed by KXA family members are:

1)  Amino acid or peptide (out)  →  Amino acid or peptide  (in).

2)  Phospholipid (inner monolayer of the plasma membrane) →  Phospholipid (outer monolayer of the plasma membrane)

References associated with 2.A.112 family:

Calenda, G., J. Peng, C.M. Redman, Q. Sha, X. Wu, and S. Lee. (2006). Identification of two new members, XPLAC and XTES, of the XK family. Gene 370: 6-16. 16431037
Chen, Y.Z., J. Mapes, E.S. Lee, R.R. Skeen-Gaar, and D. Xue. (2013). Caspase-mediated activation of Caenorhabditis elegans CED-8 promotes apoptosis and phosphatidylserine externalization. Nat Commun 4: 2726. 24225442
Ho, M., J. Chelly, N. Carter, A. Danek, P. Crocker, and A.P. Monaco. (1994). Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 77: 869-880. 8004674
Jung, H.H., A. Danek, and B.M. Frey. (2007). McLeod syndrome: a neurohaematological disorder. Vox Sang 93: 112-121. 17683354
Lee, S., D. Russo, and C. Redman. (2000). Functional and structural aspects of the Kell blood group system. Transfus Med Rev 14: 93-103. 10782495
Peng, J., C.M. Redman, X. Wu, X. Song, R.H. Walker, C.M. Westhoff, and S. Lee. (2007). Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases. Gene 392: 142-150. 17300882
Sivagnanam, U., S.K. Palanirajan, and S.N. Gummadi. (2017). The role of human phospholipid scramblases in apoptosis: An overview. Biochim. Biophys. Acta. 1864: 2261-2271. 28844836
Suzuki, J. and S. Nagata. (2014). Phospholipid scrambling on the plasma membrane. Methods Enzymol 544: 381-393. 24974298
Suzuki, J., D.P. Denning, E. Imanishi, H.R. Horvitz, and S. Nagata. (2013). Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341: 403-406. 23845944
Suzuki, J., E. Imanishi, and S. Nagata. (2014). Exposure of phosphatidylserine by Xk-related protein family members during apoptosis. J. Biol. Chem. 289: 30257-30267. 25231987
Suzuki, J., E. Imanishi, and S. Nagata. (2016). Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc. Natl. Acad. Sci. USA 113: 9509-9514. 27503893
Zhang, P., M. Maruoka, R. Suzuki, H. Katani, Y. Dou, D.M. Packwood, H. Kosako, M. Tanaka, and J. Suzuki. (2023). Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4. Nat Commun 14: 5592. 37696806