Nectins and Nectin-like molecules (Necl) are families of

cellular adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the molecular binding, binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help ce ...

s involved in Ca²⁺-independent

cellular adhesion Cell adhesion is the process by which cells interact and attach to neighbouring cells through specialised molecules of the cell surface. This process can occur either through direct contact between cell surfaces such as cell junctions or indire ...

. Nectins are ubiquitously expressed and have adhesive roles in a wide range of tissues such as the

adherens junction Adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions, cell–matrix junctions in epithelial and endothelial tissues, usually more basal than tight junctions. ...

epithelia Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

or the

chemical synapse Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syst ...

of the neuronal tissue.

Diversity

So far four nectins have been identified in humans, namely

nectin-1 Poliovirus receptor-related 1 (PVRL1), also known as nectin-1 and CD111 (formerly herpesvirus entry mediator C, HVEC) is a human protein of the immunoglobulin superfamily (IgSF), also considered a member of the nectins. It is a membrane protein w ...

nectin-2 Poliovirus receptor-related 2 (PVRL2), also known as nectin-2 and CD112 (formerly herpesvirus entry mediator B, HVEB), is a human plasma membrane glycoprotein. Function This gene encodes a single-pass type I membrane glycoprotein with two Ig-lik ...

, nectin-3 and nectin-4. These four family members have also been found in most other well studied mammals. Also, five Necls have been identified, these are: Necl-1, Necl-2, Necl-3, Necl-4 and Necl-5.

Structure

All nectins and all Necls share the same overall structure defined by three extra cellular

immunoglobulin domain The immunoglobulin domain, also known as the immunoglobulin fold, is a type of protein domain that consists of a 2-layer sandwich of 7-9 antiparallel β-strands arranged in two β-sheets with a Greek key topology, consisting of about 125 amino a ...

s, a single transmembrane helix and an intracellular domain. For all nectins the intracellular domain can bind a

scaffold protein In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...

named afadin (the product of the

MLLT4 Afadin is a protein that in humans is encoded by the ''AFDN'' gene. Function Afadin is a Ras (see HRAS; MIM 190020) target that regulates cell–cell adhesions downstream of Ras activation. It is fused with MLL (MIM 159555) in leukemias caused ...

gene). All nectins and Necls can form homo-cis dimers, meaning a dimer of two alike molecules on the same cell membrane. Following the homo-dimer formation they can trans-interact in an either heterophilic or homophilic manner. The network of the nectin and Necl trans-interactions has been characterized. Recent structural reports reveal the physical and chemical determinants of homophilic interactions mediated by N-terminal IgV domains. In general, heterophilic interactions among nectins have higher affinity than their respective homophilic interactions. Nectins and Necls can also recruit

cadherin Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...

s to enhance binding.

Nomenclature controversy

Since the research of nectins has been approached from several angles there is still some controversy about the names of these proteins and the genes encoding them. The idea of grouping these proteins into nectins and Necls originates from Dr. Youhsimi Takais early studies of the proteins. Nectins and Necls are much related in function and protein structure and have been found to interact in a variety of way, which it is why it makes good sense to define them as families. However, if you consider the sequence of the genes encoding the proteins an alternative way of naming the proteins also make sense as pointed out by Thomas Biederer. Alternative names for nectins and Necls are listed below. nectin-1 :

PVRL1 Poliovirus receptor-related 1 (PVRL1), also known as nectin-1 and CD111 (formerly herpesvirus entry mediator C, HVEC) is a human protein of the immunoglobulin superfamily (IgSF), also considered a member of the nectins. It is a membrane protein ...

(Poliovirus receptor-related 1), HveC (herpesvirus entry mediator C), CD111 (Cluster of Differentiation 111) nectin-2 :

PVRL2 Poliovirus receptor-related 2 (PVRL2), also known as nectin-2 and CD112 (formerly herpesvirus entry mediator B, HVEB), is a human plasma membrane glycoprotein. Function This gene encodes a single-pass type I membrane glycoprotein with two Ig- ...

(Poliovirus receptor-related 2), HveB (herpesvirus entry mediator B), CD112 (Cluster of Differentiation 112) nectin-3 :

PVRL3 Nectin-3, also known as nectin cell adhesion molecule 3, is a protein that in humans is encoded by the ''NECTIN3'' gene. Nectin-3 belongs to the family of immunoglobulin(Ig)-like cellular adhesion molecules involved in Ca2+-independent cellular ...

(Poliovirus receptor-related 3), CD113 (Cluster of Differentiation 113) nectin-4 : PVRL4 (Poliovirus receptor-related 4), LNIR; PRR4; EDSS1 Nectin 4 – cell adhesion molecule 4
/ref> necl-1 :

CADM3 Cell adhesion molecule 3 is a protein that in humans is encoded by the ''CADM3'' gene. IGSF4B is a brain-specific protein related to the calcium-independent cell-cell adhesion molecules known as nectin Nectins and Nectin-like molecules (Necl) a ...

(Cell adhesion molecule 3), TSLL1 (TSLC1-like 1), SynCAM3 (Synaptic cell adhesion molecule 3), IGSF4B (Immunoglobulin super family member 4B) necl-2 :

CADM1 Cell adhesion molecule 1 is a protein that, in humans, is encoded by the ''CADM1'' gene. Model organisms Model organisms have been used in the study of CADM1 function. A conditional knockout mouse line, called ''Cadm1tm1.2Brd'' was generated. Ma ...

(Cell adhesion molecule 1), TSLC1 (Tumor suppressor in lung cancer 1), SynCAM1 (Synaptic cell adhesion molecule 1), IGSF4 (Immunoglobulin super family member 4), sgIGSF (Spermatogenic immunoglobulin superfamily), RA175 necl-3 : SynCAM2 (Synaptic cell adhesion molecule 2) necl-4 : TSLL2 (TSLC1-like 2), SynCAM4 (Synaptic cell adhesion molecule 1) necl-5 : Tage4, PVR (Poliovirus receptor), CD155

Clinical relevance

Nectin-1 and nectin-3 have been shown to be involved in cellular adhesion in some neuronal synapses. Unlike many other cellular adhesion molecules they do not distribute evenly on axonal and dendritic side of the synapse. Instead, Nectin-1 is primarily found on the axonal side and nectin-3 primarily on the dendritic side. Nectin-1 serves as the entry receptor for Herpes Simplex Viruses 1 and 2, binding to the viral envelope glycoprotein gD, and for Pseudorabies Virus. Recently, it has been found that nectin-4 can be found in the serum of patients with lung cancer. This has led to speculations that this protein might be involved in some developing cancers and might even have a pharmaceutical potential. Also, it has been well known for some time now, that necl-2 is down regulated in a variety of cancers. This is why necl-2 is also known as Tumor suppressor in lung cancer 1 (TSLC1).

As a drug target

Nectin-4 : Enfortumab vedotin-ejfv was approved by the FDA in 2019; it is a Nectin-4-directed antibody drug conjugate that has shown clinical activity in metastatic urothelial cancer.

References

{{Cell adhesion molecules Cell adhesion molecules