• AlphaL integrin chain
• LFA-1alpha

MAJOR LINKS FOR CD11a  

• NCBI LocusLink Record: 3683
• Mendelian Inheritance in Man (OMIM): 153370
• SwissProt annotated protein record: P20701

• Ligand binding, leukocyte intercellular adhesions, and costimulatory signaling. See previous and next sections

CELLULAR FUNCTION OF CD11a  

• Recognized functions are intercellular adhesion and costimulation
• 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 zero 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 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

DISEASE RELEVANCE OF CD11a AND FUNCTION OF CD11a IN INTACT ANIMAL  

• Most immune/inflammatory responses and effector functions involve leukocyte adhesions, often depending critically on CD11a/CD18. See section Cellular Function for examples
• 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), reduce or prevent expression of leukocyte integrins. This can cause profound immunodeficiency, often fatal in the first two years of life
• Antibodies to CD11a, CD18, or ICAM-1 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

• Families in which CD11a is a member
  • CD11a-->integrin alpha chains-->integrin assemblies

MOLECULAR STRUCTURE OF CD11a  

• Expressed as heterodimer CD11a/CD18, noncovalently linked
• Type I transmembrane protein
• 1145 amino acids
• 1063 amino acid extracellular region
• 29 amino acid transmembrane region
• 53 cytoplasmic region
• The boundary between the transmembrane sequence and the cytoplasmic domain contains the sequence VGFFKR, important for heterodimerization and regulation of function
• The extracellular moiety contains seven repeats of about 50 amino acids each *The repeat at the membrane-distal end of the sequence is numbered "1"; repeats 1-2 and 3-7 are in tandem
• Repeats five, six, and seven contain EF-hand-like sequences believed to bind divalent metal cations
• These seven repeating sequences have been modeled to resemble a beta-propeller fold similar to the beta subunit of the trimeric G proteins
• Between the second and third repeated domains is an inserted/interactive or "I" domain of about 200 amino acids
• The crystal structure of the LFA-1 I domain has been solved and resembles an alpha-beta dinucleotide binding fold
• The I domain contains a discontinuous metal ion-dependent adhesion site (MIDAS) with sequence DxSxS...T...N (where x is any amino acid)
• One of the six 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, e.g. Glu34 in ICAM-1

MOLECULAR MASS OF CD11a  

POST-TRANSCRIPTIONAL MODIFICATION OF CD11a   - No information

POST-TRANSLATIONAL MODIFICATION OF CD11a  

• 12 potential N-glycosylation sites

SUBSTRATES FOR CD11a   - No information

ENZYMES WHICH MODIFY CD11a   - No information

LIGANDS FOR CD11a AND MOLECULES ASSOCIATED WITH CD11a  

• CD11a/CD18 binds to ICAM-1 (CD54), ICAM-2 (CD102), and ICAM-3 (CD50)
• Two ICAM-like molecules, ICAM-4/LW blood group antigen and ICAM-5/telencephalin, should be further investigated for leukocyte integrin reactivity
• Antibody blocking results are consistent with there being no additional ligands
• Although some non-leukocyte integrins require the RGD sequence in their ligand binding sites (e.g. 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, possibly 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

• Expressed on all leukocytes including B and T lymphocytes, monocytes, macrophages, neutrophils, basophils, and eosinophils*
• Absent from non-hematopoietic tissues and human platelets*

• All integrins have heterodimeric structure, and function in cell adhesion
• Groups of integrin alpha (heavy) chains share the same beta (light) chain
• Integrin beta chains are numbered 1 through 7 (or higher)
• Leukocyte integrins CD11a, CD11b, CD11c, CD11d share beta chain CD18, also called integrin beta-2
• CD11a is sometimes called alpha-L (for alpha heavy chain of LFA-1)
• CD18 is also called beta-2 (for beta light chain two of the integrin superfamily)
• CD11a/CD18 is most often called LFA-1 for lymphocyte (or leukocyte) function-associated antigen one; or occasionally alpha-L/beta-2. It is a member of the leukocyte integrin superfamily (see section 10 below)

SELECTION OF OTHER CD11a-SPECIFIC REFERENCE MAB  

• Many CD11a mAbs react with the isolated I domain of LFA-1

REVIEWS

1. Bergelson JM and Hemler ME. Integrin-ligand binding. Do integrins use a 'MIDAS touch' to grasp an Asp? Curr. Biol. 1995 5:615 PubMed

2. Hogg, N., R. C. Landis, P. A. Bates, P. Stanley, A. M. Randi. 1994, Trends in Cell Biol. 4:379-382

3. Lub M, van Kooyk Y and Figdor CG. Ins and outs of LFA-1. Immunol. Today 1995 16:479 PubMed

4. Martz, E. Leukocyte function-associated antigen one (LFA-1). 1997. Encyclopedia of Immunology, 2nd ed., Ivan M. Roitt and Peter J. Delves, eds. Academic Press, London, in press.

5. Parsons JT. Integrin-mediated signalling: regulation by protein tyrosine kinases and small GTP-binding proteins. Curr. Opin. Cell Biol. 1996 8:146 PubMed

6. Petty HR and Todd RF 3d. Integrins as promiscuous signal transduction devices. Immunol. Today 1996 17:209 PubMed

7. Sanchez-Mateos P, Cabanas C and Sanchez-Madrid F. Regulation of integrin function. Semin. Cancer Biol. 1996 7:99 PubMed

8. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994 76:301 PubMed

9. Stewart M, Thiel M and Hogg N. Leukocyte integrins. Curr. Opin. Cell Biol. 1995 7:690 PubMed

PRIMARY CITATIONS

10. Dustin ML and Springer TA. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature 1989 341:619 PubMed

11. Larson RS, Corbi AL, Berman L and Springer T. Primary structure of the leukocyte function-associated molecule-1 alpha subunit: an integrin with an embedded domain defining a protein superfamily. J. Cell Biol. 1989 108:703 PubMed

12. Lee JO, Bankston LA, Arnaout MA and Liddington RC. Two conformations of the integrin A-domain (I-domain): a pathway for activation? Structure 1995 3:1333 PubMed

13. Qu A and Leahy DJ. Crystal structure of the I-domain from the CD11a/CD18 (LFA-1, alpha L beta 2) integrin. Proc. Natl. Acad. Sci. U.S.A. 1995 92:10277 PubMed

14. Qu A and Leahy DJ. The role of the divalent cation in the structure of the I domain from the CD11a/CD18 integrin. Structure 1996 4:931 PubMed

15. Schmits R, Kundig TM, Baker DM, Shumaker G, Simard JJ, Duncan G, Wakeham A, Shahinian A, van der Heiden A, Bachmann MF, Ohashi PS, Mak TW and Hickstein DD. LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor. J. Exp. Med. 1996 183:1415 PubMed

16. Springer TA. Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain. Proc. Natl. Acad. Sci. U.S.A. 1997 94:65 PubMed

WWW RESOURCES

Portions copyright by Garland Press and by the International Workshops on Human Leukocyte Differentiation Antigens; used with permission

Modified 10/14/99   mpr@mail.nih.gov