Neural cell adhesion molecule 1 (NCAM1), also called NCAM or CD56, is a protein that in humans is encoded by the NCAM1gene (previously NCAM). It is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM1 has been implicated as having a role in cell–cell adhesion, neurite outgrowth, synaptic plasticity, and learning and memory.
Forms, domains and homophilic binding
NCAM1 is a glycoprotein of the Immunoglobulin (Ig) superfamily.
At least 27 alternatively spliced NCAM1 mRNAs are produced, giving a wide diversity of NCAM1 isoforms. The three main isoforms of NCAM1 vary only in their cytoplasmic domain:
NCAM-120kDa (GPI anchored)
NCAM-140kDa (short cytoplasmic domain)
NCAM-180kDa (long cytoplasmic domain)
The extracellular domain of NCAM1 consists of five immunoglobulin-like (Ig) domains followed by two fibronectin type III (FNIII) domains. The different domains of NCAM1 have been shown to have different roles, with the Ig domains being involved in homophilic binding to NCAM1, and the FNIII domains being involved signalling leading to neurite outgrowth.
Homophilic binding occurs between NCAM1 molecules on opposing surfaces (trans-) and NCAM1 molecules on the same surface (cis-)1. There is much controversy as to how exactly NCAM1 homophilic binding is arranged both in trans- and cis-. Current models suggest trans- homophilic binding occurs between two NCAM1 molecules binding antiparallel between all five Ig domains or just IgI and IgII. cis- homophilic binding is thought to occur by interactions between both IgI and IgII, and IgI and IgIII, forming a higher order NCAM1 multimer. Both cis- and trans- NCAM1 homophilic binding have been shown to be important in NCAM1 "activation" leading to neurite outgrowth.
Minor exons
Another layer of complexity is created by the insertion of other "minor" exons in the NCAM1 transcript. The two most notable are:
the VASE (VAriable domain Spliced Exon) exon which is thought to correlate with an inhibition of the neurite outgrowth promoting properties of NCAM1.
the MSD (Muscle Specific Domain), which is thought to play a positive role in myoblast fusion. In skeletal muscle it is found in all three NCAM1 isoforms, increasing their MW, giving NCAM-125, NCAM-145, and NCAM-185 isoforms, but is most commonly found in the NCAM-125 isoform.
Posttranslational modification
NCAM1 exhibits glycoforms as it can be posttranslationally modified by the addition of polysialic acid (PSA) to the fifth Ig domain, which is thought to abrogate its homophilic binding properties and can lead to reduced cell adhesion important in cell migration and invasion. PSA has been shown to be critical in learning and memory. Removal of PSA from NCAM1 by the enzyme endoneuraminidase (EndoN) has been shown to abolish long-term potentiation (LTP) and long-term depression (LTD).
Later in development, NCAM1 (CD56) expression is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle.
NCAM1 has been identified as one of the target proteins for both the rabies and zika virus, allowing entry into the cell.
Anti-NCAM1 therapy
NCAM1 has been used as a target molecule for experimental antibody-based immunotherapy. Successful radio-immunolocalisation of metastases was demonstrated after giving injections of NCAM1-binding 123J-UJ13a or 131J-UJ13a radio-immunoconjugates to children with neuroblastoma. Patients with small cell lung cancer were treated with the anti-NCAM1 immunotoxin huN901-DM1 in two different clinical studies, revealing acceptable toxicity and signs of clinical response.
↑Becker CG, Artola A, Gerardy-Schahn R, Becker T, Welzl H, Schachner M (July 1996). "The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation". Journal of Neuroscience Research. 45 (2): 143–52. doi:10.1002/(SICI)1097-4547(19960715)45:2<143::AID-JNR6>3.0.CO;2-A. PMID8843031. S2CID43042018.
↑Stoenica L, Senkov O, Gerardy-Schahn R, Weinhold B, Schachner M, Dityatev A (May 2006). "In vivo synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid". The European Journal of Neuroscience. 23 (9): 2255–64. doi:10.1111/j.1460-9568.2006.04771.x. PMID16706834. S2CID22798537.
1epf: CRYSTAL STRUCTURE OF THE TWO N-TERMINAL IMMUNOGLOBULIN DOMAINS OF THE NEURAL CELL ADHESION MOLECULE (NCAM)
1lwr: Solution structure of the NCAM fibronectin type III module 2
1qz1: Crystal Structure of the Ig 1-2-3 fragment of NCAM
2e3v: Crystal structure of the first fibronectin type III domain of neural cell adhesion molecule splicing isoform from human muscle culture lambda-4.4
2haz: Crystal structure of the first fibronectin domain of human NCAM1
