| Aspect | Key findings for human CD33 (SIGLEC3; UniProt P20138) | Evidence/Citation |
|---|---|---|
| Verified identity | CD33 is the human myeloid cell surface antigen also called Siglec-3, a member of the CD33-related Siglec family within the immunoglobulin superfamily; this matches the UniProt target description and distinguishes it from unrelated genes. | (pqac-00000001, pqac-00000006) |
| Protein class and overall architecture | Single-pass type I transmembrane receptor with an extracellular region containing 2 Ig-like domains, a transmembrane helix, and a cytoplasmic tail. The extracellular domains are an N-terminal V-set Ig domain for glycan recognition and one C-set/C2-set Ig-like domain contributing to structure and receptor organization. | (pqac-00000001, pqac-00000004, pqac-00000010) |
| Structural/domain details | CD33 is among the smallest Siglecs because it contains only one IgC domain after the IgV domain. Recent structural work supports an IgC1 homodimerization interface, a 21-residue mostly monomeric transmembrane helix, and a dynamically unstructured cytosolic domain. | (pqac-00000001, pqac-00000000, pqac-00000005) |
| Extracellular domain boundaries used experimentally | A recent structural study expressed human CD33 extracellular domain as residues 1-232, supporting the two-domain ectodomain organization used in biochemical and crystallographic analyses. | (pqac-00000008) |
| Sialic acid-binding site | The glycan-binding site is centered on a conserved Arg119 that ligates the sialic acid carboxylate. Binding is further stabilized by an aromatic cluster including Phe21, His45, and Tyr127 and by the STKYSYK motif spanning residues 124-130. | (pqac-00000004) |
| Glycan/substrate specificity | CD33 recognizes terminal sialic acids on sialoglycans rather than catalyzing a reaction. Siglecs in general discriminate among α2-3, α2-6, and α2-8 linkages and underlying glycan context; for CD33, available structural and functional evidence supports preference for α2-6-linked sialoglycans and also binding to the sulfated sialylated trisaccharide Neu5Acα2-3[6SO3]Galβ1-4GlcNAc. | (pqac-00000003, pqac-00000001, pqac-00000004) |
| Physiologic and disease-relevant ligands | Reported physiological ligands include keratan sulfate proteoglycans in the brain. In chronic hepatitis B work, α2,6-biantennary sialoglycans on HBsAg bind CD33 directly and trigger inhibitory signaling. | (pqac-00000001, pqac-00000008) |
| Ligand-binding mode | CD33 recognizes self-associated sialoglycans as part of immune self/non-self discrimination. Multivalency and receptor clustering are likely important for productive signaling. | (pqac-00000001, pqac-00000002, pqac-00000003) |
| Cellular localization | Cell-surface receptor on the plasma membrane of myeloid-lineage cells; antibody cross-linking can relocalize CD33 to lipid raft membrane domains. | (pqac-00000001, pqac-00000000) |
| Cell-type expression | Expressed on myeloid progenitors, monocytes, macrophages, mast cells, dendritic cells, and brain microglia; disease/atlas-style summaries also list leukemias and myelodysplastic syndromes among contexts where these expressing cells are clinically important. | (pqac-00000001, pqac-00000007) |
| Cytoplasmic signaling motifs | CD33 contains one ITIM and one ITIM-like motif in its cytoplasmic tail; inhibitory Siglecs use these phosphotyrosine motifs to recruit phosphatases after receptor engagement. | (pqac-00000001, pqac-00000010) |
| Proximal signaling mechanism | Upon ligand engagement or appropriate crosslinking, CD33 ITIM motifs become phosphorylated and recruit SHP-1 and/or SHP-2 phosphatases, attenuating activating pathways and suppressing cell activation. HBV-associated studies specifically describe ITIM phosphorylation followed by SHP-1/2 recruitment. | (pqac-00000004, pqac-00000008, pqac-00000010) |
| SHP phosphatase coupling | Human AD-focused work emphasizes CD33-SHP-1/PTPN6 interaction, including genotype-dependent differences in microglia-like cells, while broader Siglec studies and HBV work support SHP-1 and SHP-2 recruitment capability. | (pqac-00000012, pqac-00000004, pqac-00000010) |
| Relationship to activating pathways | CD33 functions as an inhibitory checkpoint that counterbalances ITAM/DAP12-SYK/MAPK-type activation pathways. In microglia, CD33 loss or signaling disruption increases SYK and ERK1/2 phosphorylation and enhances phagocytosis, consistent with antagonism of activating receptors such as TREM2-associated pathways. | (pqac-00000009, pqac-00000010) |
| Primary biological function | Immune inhibitory receptor that senses sialoglycans and dampens myeloid-cell activation. In the CNS, CD33 modulates microglial responses, including phagocytosis of amyloid-β and inflammatory output; in peripheral myeloid cells it contributes to inhibitory checkpoint control. | (pqac-00000001, pqac-00000009, pqac-00000011) |
| Functional consequences of reduced CD33 signaling | CD33 knockout or exon-2-deleted CD33 expression in human macrophages/microglia increases inflammatory-pathway transcription, SYK and ERK1/2 phosphorylation, and phagocytosis of aggregated Aβ1-42 and bacterial particles; oxidative burst rises after knockout but not necessarily after the short isoform. | (pqac-00000009) |
| Alzheimer’s disease genetics | CD33 is an AD susceptibility locus. The rs3865444C risk allele is associated with increased surface density/full-length CD33 on myeloid cells and reduced Aβ phagocytosis, while the protective haplotype involving rs12459419T favors exon 2 skipping and production of the short isoform lacking the canonical sialic acid-binding IgV domain. | (pqac-00000012, pqac-00000009) |
| AD isoforms and function | Full-length CD33M is generally inhibitory and associated with increased Aβ burden, whereas the short isoform CD33m/CD33ΔE2 is AD-protective and can enhance phagocytosis or plaque compaction despite lacking the canonical exon 2-encoded binding domain. | (pqac-00000009) |
| Therapeutic relevance in AD | AAV-mediated knockdown of CD33 in APP/PS1 mice reduced CD33 mRNA, soluble Aβ40/Aβ42, plaque burden, and neuroinflammatory readouts, supporting CD33 as a therapeutic target for microglial reprogramming in AD. | (pqac-00000011) |
| Hematologic malignancy relevance | CD33 is a lineage marker on myeloid leukemias and a validated therapeutic target in acute myeloid leukemia; this clinical use reflects stable cell-surface expression on malignant myeloid cells rather than an enzymatic activity. | (pqac-00000001, pqac-00000002, pqac-00000007) |
| Additional disease context | CD33 has also been implicated as an inhibitory receptor exploited by HBV, where viral HBsAg-associated α2,6 sialoglycans engage CD33 to promote immune tolerance in myeloid cells. | (pqac-00000004, pqac-00000008) |


*Table: This table summarizes the verified identity, structure, ligand specificity, localization, signaling mechanism, core functions, and disease relevance of human CD33/Siglec-3. It is useful as a compact evidence map for functional annotation of the gene product.*