L1 (protein)

Source: Wikipedia, the free encyclopedia.
L1CAM
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_024003
NM_000425
NM_001143963
NM_001278116

NM_008478
NM_001374694

RefSeq (protein)

NP_000416
NP_001137435
NP_001265045
NP_076493

n/a

Location (UCSC)Chr X: 153.86 – 153.89 MbChr X: 72.9 – 72.94 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

L1, also known as L1CAM, is a

neurons
.

Mutations in the L1 protein are the cause of L1 syndrome, sometimes known by the acronym CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus).[6]

Tissue and cellular distribution

L1 protein is located all over the nervous system on the surface of neurons. It is placed along the cellular membrane so that one end of the protein remains inside the nerve cell while the other end stays on the outer surface of the neurone. This position allows the protein to activate chemical signals which spread through the neurone.[7]

There are a wide variety of cells which express the protein L1, not only neuronal cells but also some non-neuronal ones.

Purkinje cells. Finally, it is expressed in multiple tumor cells for example Melanoma and lung carcinoma cells.[5]

L1CAM is also frequently used as a marker of Extracellular Vesicles (EVs) originating from neuronal cells, although its presence specifically on neuron-derived EVs is debatable.[9]

Gene

The human L1CAM gene is found in X chromosome regions that are implicated in different neuromuscular diseases, and near the one associated with mental retardation. L1CAM gene is located in the long arm of X chromosome in Xq28 position.[10][11]

Location of L1CAM gene

Structure

immunoglobulin domains followed by five fibronectin type III domains which are connected to a small intracellular domain by a transmembrane helix. The human protein is very similar to the one that is found in mice (they are 92% identical at amino acid level, this enabling the scientists to study its structure. There are other CAM proteins like Ng-CAM (found in chicken) which has lower similarities to the human one (they are 40% identical at the amino acid level). The comparative of the sequences from human, mouse, chick and Drosophila and its good conservation, indicates that the L1 immunoglobulin domain 2 and fibronectin type III domain 2 probably are functionally important.[12][13]

Function

L1 is an important protein for the development of the nervous system affecting both cell adhesion and motility.

Cell adhesion

L1 has a static function as a

neurons and in the growth and association of neurites called neurite fasciculation.[14]

Cell motility

Motility promoting functions are related to the regulation of the movement of nerve cells during

neural development. L1 is present in developing neurons and plays an important role in guiding new neurons into the correct positions and helping axons grow and make connections with other neurons. L1 is also involved in synaptic plasticity
, which is the ability of synapses to strengthen or weaken, and it also plays a role in regeneration after trauma.

Some studies have proved that L1 has a role in tumor growth, tumor cell invasion, metastasis of melanoma, ovarian and colon cancer[15] due to an overexpression of the protein L1 that improves cell motion of the malignant cells.

The domains of this protein promote homophilic interactions, where adhesion molecules on one cell interact with identical molecules on the other cell. And also heterophilic interactions, where an adhesion molecule on one cell works as a receptor that connects with a different molecule on the other cell.[16][17] These interactions promote cell adhesion and regulation of signal transduction.

In addition, L1 participates in myelination processes, which are involved in the proliferation of myelin through the nervous system (specifically the progressive myelination of nerve axon fibers), by mediating the elongation of

Schwann cells
along the axon.

Nervous system

L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on

spastic paraplegia. Lower limb spasticity, mental retardation, hydrocephalus and flexion deformity of the thumbs are some of the symptoms expressed mostly in male individuals who suffer from this condition.[19][20][21] Although the pathological mechanisms leading to L1 syndrome are still unknown, about 200 mutations of the L1CAM gene have been identified and then associated with the syndrom. These mutations mostly affect structurally important key residues in the extracellular region of L1 causing alterations in the protein binding properties, which correlate to the impairment of neuronal physiological mechanisms such as cell adhesion or specific interacting with other molecules.[22] Ankyrin interaction with L1CAM is an example of a protein binding that fails in CRASH patients[23] due to a mutation that causes leucine and histidine to replace serine and tyrosine respectively, in the SFIGQY motif, where ankyrin should be bound in the L1CAM family cytoplasmic terminus.[24][25] Ankyrin-L1CAM interaction is involved in the growth cone
initiation, consequently, a failure in this interaction causes neurites to not reach synaptic target.

Furthermore, evidence shows there is a correlation between fetal alcohol spectrum disorder and L1 protein since ethanol inhibits L1-mediated adhesion and neurite outgrowth.[26] Hirschsprung's disease has also been linked to a L1CAM malfunction.[27]

Transcription and synthesis

The gene that regulates L1CAM transcription is found in

exons (in front of a non-translated exon 0 and next to the first protein-coding exon 1).[31] SLUG (SNAI2), a transcription factor, upregulates the expression of L1CAM.[32]

Sequences and different isoforms

L1CAM different isoforms (1, 2 and 3)
L1CAM different isoforms (1, 2 and 3)

L1CAM has three different

canonical sequence.[33] The main difference between them is where they can be found, for example, the full-length isoform (isoform 1), is the one usually found in neural cells, while the short one or nonneural isoform (isoform 2), is predominant in the other cell types.[34]

Length (n aa) Mass (Da) Sequence
Isoform 1

(fl-L1)

1,257 140,003
Canonical sequence
.
Isoform 2

(sh-L1)

1,253 139,517 Differs from the
canonical sequence
in the amino acids between position 1177 and 1180, which aren't found in this isoform.
Isoform 3 1,248 138,908 Differs from the
canonical sequence in the amino acids between position 26 and 31 where six amino acids are exchanged for a leucine and as the previous one, in the amino acids between position 1177 and 1180, which aren't found in this isoform.[35]

Interactions

L1 (protein) has been shown to

Ig-like domain interactions

L1CAM is capable of folding into a horseshoe configuration by the establishment of homophilic interactions within Ig-like domains of the same protein (the first and the second Ig motifs folding back onto the 4th and 3rd motifs). This conformation is essential for L1CAM being able to interact with other molecules and subsequently performing some of its most important functions.

Ig-like domains are implicated in many homophilic interactions with other L1CAM proteins located in adjacent cells. L1CAM molecules interact via the Ig (1-4)-like domains, allowing cell to cell adhesion. They are also important in the formation of heterophilic interactions with

receptor tyrosine kinases
(specially during the development of the nervous system).

The six Ig motif of the L1 protein contains an Arg-Gly-Asp sequence which allows binding with diverse surface cell integrins. This interaction leads to a signaling cascade which activates focal adhesion kinases (FAK) which are then converted to its active state and form the FAK/SRC complex. The latest functions as an activator of mitogen-activated protein kinases. Another function derived from integrin binding is the activation of NF-κB which results in making cells more motile and invasive.[5]

Fibronectin domain interactions

Fibronectin domains of L1 protein are also capable of binding cell surface integrins. They interact with fibroblast growth factor receptor 1, which suggests it may be linked to the modulating of neuronal differentiation.[5]

Cytoplasmic tail interactions

The most important binding partners of the cytoplasmic tail of L1 proteins are ankyrins. The interaction is held in high-affinity binding sites located within the so-called “ank repeats” also known as membrane-binding domains.[5] This interaction allows L1 protein connect with the cell's cytoskeleton. Also, L1 protein cytoplasmic tail can bind adaptor 2 (ADP), a key component of clathrin mediated endocytosis.

The fact this region contains some phosphorylation sites suggests L1 may be subject to regulation by kinases.[5]

Implications in cancer metastasis

L1CAM protein expression is normally restricted to neurons. However, it has been noticed there's L1CAM overexpression in all types of cancer cells, which has been associated with poor prognosis, tumor progression and metastasis.[37] This up-regulation may not be necessarily associated with mutations in L1 transcription factors. It has been seen this protein plays a key role in inflammatory reactions as the ones taking place in the tissue surrounding a tumor. This could explain why this protein gets suddenly overproduced in tumor cells. L1CAM's diverse functions make tumor cells more aggressive and resistant. Their migratory and motility related functions may result key in cell epithelial–mesenchymal transition (EMT) allowing cells to lose cell to cell static junctions and apico-basal polarity leading to them becoming migratory and independent. Also, its capacity to form adhesive interactions within different cell types may result in an advantage for tumor cells when it comes to co-opt and invade the surrounding tissues or capillaries.

Once tumor cells become anchorage-independent and migratory, due to L1 up-regulation, they leave the tissue where they belong and migrate through the capillaries to other organs. One frequent destination of tumor cells is the brain. So to settle in the brain, tumor cells have to succeed in crossing the blood brain barrier (BBB) where they get exposed to the plasmin secreted by astrocytes. Plasmin breaks L1CAM and inhibits the malignant cell's migrating powers. However, recent studies have noted these cancer cells overproduce anti-PA serpins, which are the usual inhibitors of plasmin, allowing them to cross the BBB and succeed in metastasis.[37]

Possible therapies involving L1CAM

L1CAM synthesis inhibition using siRNA

Because L1CAM is considered to be a key factor in

amino acids) after transcription, so that the protein cannot be synthetised.[citation needed] Nevertheless, these possible therapies involving L1CAM as a target in human cancer are still in preclinical research.[39]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198910 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031391 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^
    PMID 27267927
    .
  6. ^ "Entrez Gene: L1CAM L1 cell adhesion molecule".
  7. ^ "L1CAM gene". Genetics Home Reference. U.S. Department of Health and Human Services.
  8. PMID 30829570
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  9. .
  10. .
  11. ^ "L1CAM Mutation Web Page". L1CAM Mutation Database. University Medical Center Groningen. 12 October 2012. Retrieved 23 October 2016.
  12. PMID 8947027
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  15. ^ "L1CAM (L1 cell adhesion molecule)".
  16. ^ Cushier A. "Cell interactions". University of Malta. Retrieved 2 October 2016.
  17. .
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  27. .
  28. ^ "L1CAM (L1 cell adhesion molecule)". Atlas of Genetics and Cytogenetics in Oncology and Hematology l. Retrieved 6 October 2016.[permanent dead link]
  29. ^ "L1CAM Gene". Gene Cards.
  30. S2CID 24858876
    .
  31. .
  32. .
  33. ^ "L1CAM - Neural cell adhesion molecule L1 precursor - Homo sapiens (Human) - L1CAM gene & protein". www.uniprot.org. Retrieved 2016-10-23.
  34. S2CID 5448318
    .
  35. ^ "L1CAM - Neural cell adhesion molecule L1 precursor - Homo sapiens (Human) - L1CAM gene & protein". UniProt. Retrieved 2016-10-23.
  36. S2CID 12118386
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  37. ^ .
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  39. .

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


Atlas of genetics and cytogenetics in oncology and haematology: http://atlasgeneticsoncology.org/Genes/L1CAMID44110chXq28.html