CD11a ITGAL (integrin α L chain), LFA-1 (heavy chain of leukocyte function associated antigen-1) gp180/95
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
Lymphocyte
Granulocyte
Monocyte
Macrophage
T Cell
Leukocyte
Eosinophil
Neutrophil
Basophil
T Lymphocyte
B Lymphocyte
Polymorphonuclear cell
170 / 170
180 / 180

Expression
CD11a is expressed on all leukocytes including B and T lymphocytes, monocytes, macrophages, neutrophils, basophils and eosinophils, on lower levels on polymorphonuclear cells but is absent on non-hematopoietic tissues and  platelets.  There is increased levels of expression on memory T cells.


Structure
MOLECULAR FAMILY NAME:  Belongs to the integrin a chain family.

CD11a is a single-pass type-1 a chain 1145 aa glycoprotein.  It contains an 1063 aa extracellular domain which contains 7 tanden domains of about 50 aa each and have been modeled to resemble a b-propeller fold similar to the b subunit of the trimeric G proteins, an I-domain and 12 glycosylation sites, a 29 aa transmembrane doman and a 53 aa cytoplasmic domain. The boundary between the transmembrane sequence and the cytoplasmic domain contains the sequence VGFFKR which is important for heterodimerization and regulation of function. The repeat at the membrane-distal end of the sequence is numbered "1"; repeats 1-2 and 3-7 are in tandem.  Repeats 5, 6, and 7 contain EF-hand-like sequences are believed to bind divalent metal cations.  These 7 repeating sequences have been modeled to resemble a b-propeller fold similar to the b subunit of the trimeric G proteins.  Between the 2nd and 3rd repeated domains is an inserted/interactive or "I" domain of about 200 aa.  The crystal structure of CD11a domain resembles an a-b dinucleotide binding fold.  The I domain contains a discontinuous metal ion dependent adhesion site, MIDAS, with a  sequence DxSxS...T...N, where x is any amino acid.  One of the 6 coordination sites of the MIDAS-bound metal ion is not occupied by an I domain residue.  This face of the ion is exposed at the surface of the I domain and is hypothesized to engage ligand, such as Glu34m in ICAM-1.  It is expressed as a non-covalently linked heterodimer with CD18.

MOLECULAR MASS
Cell Type Unreduced Reduced
Leukocytes 170 kDa 180 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.

POST-TRANSLATIONAL MODIFICATION

There are 12 potential N-glycosylation sites.

Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD11a

CD11a/CD18 binds to CD54 (ICAM-1), CD102 (ICAM-2), and CD50 (ICAM-3), each of which contains IgSF domains.  Ligands might be 2 ICAM-like molecules, CD242 (ICAM-4/LandsteinerWiener blood group antigen) and ICAM-5/telencephalin (CD # not assigned yet), should be further investigated for leukocyte integrin reactivity.  Antibody blocking results are consistent with there being no additional ligands.  Although some nonleukocyte integrins require the RGD sequence in their ligand binding sites like fibronectin, none of the ICAM's contain RGD.  Most antibodies to CD11a block ligand binding, but some activate ligand binding and rare antibodies have no effect on ligand binding.  The I domain is believed to contain the major ligand binding site, possible in concert with other regions, notably repeats 5 and 6 and CD18.  The CD18 in leukocyte integrins binds unopsonized bacteria E. coli and fungi Histoplasma capsulatum in a temperature and divalent cation-dependent manner, playing an important role in phagocytosis of unopsonized microbes.  Ligand binding requires magnesium.  Calcium alone does not support ligand binding.  Manganese supports ligand binding with several times the potency of magnesium.



Function
CD11a plays a central role in leukocyte intercellular cell-cell adhesion through heterophilic interactions with its ligands, ICAM-1-3 and functions in lymphocyte co-stimulatory signaling.  Physiologic ICAM-binding by CD11a/CD18 on intact cells requires magnesium, is inhibited by calcium, requires metabolic energy, requires an intact actin cytoskeleton and does not occur at 0 degrees centigrade.  Antibodies to CD11a/CD18 block T cell responses to antigen presenting cells including the mixed lymphocyte reaction, T cell help to B cells, CTL- and NK-mediated killing, macrophage killing of tumor cells, and leukocyte endothelium adhesion/extravasation.  Cells can rapidly change the functional affinity of the surface CD11a/CD18 for ICAM's without changing the surface density of CD11a/CD18.  Physiologic activation occurs via receptor-derived signals.  Experimentally, cellular CD11a/CD18 can be activated via protein kinase C phorbol esters, magnesium in the absence of calcium, or manganese.   Recent studies show CD11a is part of the immunological synapse associated with antigen recognition and T cell activation.  

BIOCHEMICAL ACTIVITY

CD11a has ligand binding, leukocyte intercellular adhesions and co-stimulatory signaling.

DISEASE RELEVANCE AND FUNCTION OF CD11a

Most immune/inflammatory responses and effector functions involve leukocyte adhesions, often depending critically on CD11a/CD18.  Lymphocyte recirculation through lymph nodes is CD11a/CD18-dependent, recirculation to gut-associated lymphoid tissue is less so.  Human inherited mutations in CD18, called leukocyte adhesion deficiency (LAD-1), results to reduce or prevent expression of leukocyte integrins.  This can cause profound immunodeficiency, often fatal in the first 2 years of life.  CD18 deficiency has also been shown to occur in cattle and dogs.  Antibodies to CD11a, CD18 or CD102 which block adhesion have shown great promise as immunosuppressive and anti-inflammatory agents in animal models of ischemia/reperfusion, autoimmunity and transplantation.  Anti-CD11a dramatically reduces graft failure for bone marrow grafts in immunodeficient children.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD11a: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD11a: No information.

ADDITIONAL INSIGHTS

All integrins have heterodimeric structure,and function in cell adhesion.  Groups of integrin a heavy chains share the same b light chain.  Integrin b chains are numbered 1 through 7 or higher.  Leukocyte integrins CD11a, CD11b, CD11c, CD11d share b chain CD18, also called integrin b2 for the light b light chain 2 of the integrin superfamily.  CD11a/CD18 is most often called LFA-1 for lymphocyte or leukocyte function associated antigen 1 or occasionally aL/b2.  It is a member of the leukocyte integrin superfamily.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 3683P20701
MouseP24063M60778
Antibodies
25.3.1   View Reactivity
38   View Reactivity
72.87   View Reactivity
BAQ11A   View Reactivity
CA11.4D3   View Reactivity
F10-150   View Reactivity
HI111   View Reactivity
HUH73A   View Reactivity
LND73A   View Reactivity
LT35   View Reactivity
LT48A   View Reactivity
MUC76A   View Reactivity
NR185   View Reactivity

Revised June 25, 2008


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