GYPC

GYPC encodes glycophorin C, an erythrocyte surface sialoglycoprotein that acts as a receptor on the red cell surface and contributes to red cell turnover and host-pathogen interaction (PMID:24652986, PMID:15801965). Glycophorin C serves as a direct rosetting receptor for Plasmodium vivax, mediating adhesion of infected erythrocytes to normocytes; antibody blockade of its BRIC 4 region and receptor knockdown both reduce rosette formation (PMID:24652986). Ligation of the glycophorin C extracellular domain triggers phosphatidylserine exposure on the outer membrane leaflet and subsequent loss of erythrocyte viability, a response that depends on an intact extracellular domain as shown by its absence in Gerbich-variant erythrocytes bearing truncating exon deletions (PMID:15801965). A single GYPC transcript yields two proteins, glycophorin C and glycophorin D, through alternative translation initiation at two start codons (PMID:19679754). Beyond these receptor and turnover roles, the intracellular interactions of glycophorin C with the membrane skeleton are referenced in the corpus only as prior knowledge and are not experimentally established within these findings (PMID:28272739).

1. 2005 Medium

   Established that engaging glycophorin C on the red cell surface is not inert but actively signals membrane reorganization, linking GPC to phosphatidylserine externalization and red cell clearance.

   Evidence Annexin V PS-binding assay after BRIC-10 ligation, with Gerbich-variant erythrocytes (Yus, Gerbich, Ls(a)) and trypsin controls mapping the requirement to the extracellular domain

   PMID:15801965

   Open questions at the time

   • The intracellular signaling pathway connecting extracellular ligation to PS exposure is not defined
   • Single-lab study without independent replication
   • Physiological ligand driving this response in vivo is unknown
2. 2009 Low

   Resolved how one gene produces two distinct glycoproteins, showing GPC and GPD arise from alternative translation initiation on a single transcript, with GPC start-codon evolution being a human-specific trait.

   Evidence Comparative genomic sequence analysis across Hominoidea, population genetics, and translation initiation codon mapping

   PMID:19679754

   Open questions at the time

   • Primarily computational/comparative analysis without direct protein-level confirmation of the two initiation products
   • Positive selection by P. falciparum invasion pressure is hypothesized, not demonstrated
   • Functional distinction between GPC and GPD not addressed
3. 2014 Medium

   Defined a host-pathogen receptor function, establishing glycophorin C as a direct receptor mediating Plasmodium vivax rosetting of infected erythrocytes to normocytes.

   Evidence Anti-CD236R (BRIC 4) Fab inhibition and CD236R knockdown of stem-cell-derived normocytes in ex vivo P. vivax rosetting assays

   PMID:24652986

   Open questions at the time

   • The parasite ligand binding glycophorin C is not identified
   • Single-lab study with two orthogonal methods but no independent confirmation
   • Structural basis of the GPC-parasite interaction unresolved
4. 2017 Low

   Characterized the molecular basis of Gerbich blood group phenotypes, mapping them to three classes of GYPC exon deletions driven by a duplication-prone homologous genomic region.

   Evidence Molecular genotyping of 29 rare Yus/Gerbich/Leach samples and sequence homology analysis of GYPC genomic regions

   PMID:28272739

   Open questions at the time

   • Protein 4.1/p55 interaction cited as prior knowledge, not experimentally confirmed here
   • Functional consequences of each deletion class on membrane stability not directly assayed
   • Structural inference of the duplication event not experimentally validated

• The intracellular signaling mechanism linking GPC extracellular ligation to phosphatidylserine exposure, and the identity of the P. vivax ligand binding GPC, remain unresolved.
• No molecular pathway connects GPC ligation to PS externalization
• No identified parasite ligand for the rosetting interaction
• No structural model of GPC engagement