VCAM1 Protein

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VCAM1 Protein

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VCAM1 Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">VCAM1 Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Vascular Cell Adhesion Molecule 1</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>VCAM1</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>739 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~81 kDa (unglycosylated); 100-110 kDa (glycosylated)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P19320</td>
</tr>
<tr>
<td class="label">PDB Structures</td>
<td>1ASJ, 1BCZ, 1DC4, 1KV2</td>
</tr>
<tr>
<td class="label">Cellular Location</td>
<td>Plasma membrane (type I transmembrane)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Immunoglobulin superfamily (IgSF)</td>
</tr>
<tr>
<td class="label">Integrin</td>
<td>Alternative Name</td>
</tr>
<tr>
<td class="label">ITGA4/ITGB1</td>
<td>VLA-4</td>
</tr>
<tr>
<td class="label">ITGA4/ITGB7</td>
<td>α4β7</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Agent</td>
</tr>
<tr>
<td class="label">VLA-4 Antagonists</td>
<td>Natalizumab</td>
</tr>
<tr>
<td class="label">VLA-4 Antagonists</td>
<td>Firategrast</td>
</tr>
<tr>
<td class="label">VLA-4 Antagonists</td>
<td>Vedolizumab</td>
</tr>
<tr>
<td class="label">Blocking Antibodies</td>
<td>Anti-VCAM1 antibodies</td>
</tr>
<tr>
<td class="label">Small Molecules</td>
<td>VCAM1-VLA-4 inhibitors</td>
</tr>
<tr>
<td class="label">Gene Therapy</td>
<td>siRNA targeting VCAM1</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/diabetes" style="color:#ef9a9a">Diabetes</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">77 edges</a></td>
</tr>
</table>

Introduction

Vcam1 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Vascular Cell Adhesion Molecule 1 (VCAM1) is a 739-amino acid type I transmembrane glycoprotein that serves as a critical mediator of leukocyte adhesion and migration across the vascular endothelium[@osborn1989]. It plays a crucial role in neuroinflammation and blood-brain barrier (BBB) dysfunction in neurodegenerative diseases. VCAM1 is predominantly expressed on activated endothelial cells and is dramatically upregulated by proinflammatory cytokines[@dustin1990].

Protein Information

Domain Structure

VCAM1 contains distinct structural domains[@koning2009]:

Extracellular Domain (20-698 aa)

Ig-like domain D1 (20-109 aa): N-terminal domain containing the primary integrin binding site[@clements1994]
Ig-like domain D2 (110-201 aa): Contributes to ligand binding
Ig-like domain D3 (202-292 aa): Provides structural framework
Ig-like domain D4 (293-387 aa): Flexible linker region
Ig-like domain D5 (388-480 aa): D4-D5 linker
Ig-like domain D6 (481-576 aa): Supports domain organization
Ig-like domain D7 (577-698 aa): C-terminal extracellular domain

Transmembrane Domain (699-723 aa)

Single α-helical membrane-spanning segment
Contains a cysteine residue important for dimerization

Cytoplasmic Tail (724-739 aa)

Short cytoplasmic domain
Contains motifs for protein trafficking and localization

Molecular Function

Receptor Binding

VCAM1 binds primarily to the integrin α4β1 (VLA-4) and α4β7[@elices1990]:

The D1 Ig-like domain contains the primary binding site for VLA-4, involving metal ion-dependent adhesion sites (MIDAS)[@clements1994].

Biological Functions

Leukocyte adhesion: Mediates firm adhesion of circulating leukocytes to activated endothelium[@dustin1990]
Transendothelial migration: Facilitates diapedesis across the blood-brain barrier[@muller2003]
Cell survival: VCAM1-VLA-4 interaction provides pro-survival signals through PI3K/Akt pathway[@mould2002]
Angiogenesis: Supports new blood vessel formation in inflammation[@garmysusini2005]

Post-Translational Modifications

Glycosylation

VCAM1 is extensively N-glycosylated at multiple asparagine residues[@yoshida1996]:

N-glycosylation is essential for proper protein folding
Critical for ligand binding affinity
Affects receptor interactions

Proteolytic Processing

Shedding: Metalloproteinases can cleave the extracellular domain[@gough1998]
Soluble VCAM1 (sVCAM1): Released form used as inflammatory biomarker

Structural Insights

Crystal Structures

Key structural studies reveal[@clements1994][@chiu2001]:

1ASJ: VCAM1 D1-D4 domains
1BCZ: VCAM1 D1 with VLA-4
1DC4: VCAM1 D1-D7 complete ectodomain
1KV2: VCAM1-VLA-4 complex

Domain Organization

The seven Ig-like domains are arranged in a linear fashion with flexible interdomain linkers, allowing simultaneous engagement of multiple ligands and receptors[@wang2005].

Role in Neurodegenerative Diseases

Alzheimer's Disease (AD)

VCAM1 contributes significantly to AD pathogenesis[@grammas2011][@iadecola2017]:

[BBB](/entities/blood-brain-barrier) dysfunction: Elevated expression on brain endothelial cells disrupts the blood-brain barrier[@zlokovic2008]
Immune cell infiltration: Mediates peripheral immune cell trafficking into the brain[@michaud2013]
Cerebral amyloid angiopathy (CAA): Associated with vascular amyloid deposits[@weller2009]
Neurovascular coupling: Dysregulation affects cerebral blood flow regulation[@blair2020]
Pericyte function: Affects pericyte coverage and BBB integrity[@sweeney2019]

Parkinson's Disease (PD)

In PD, VCAM1 mediates neuroinflammation[@zhang2019][@chen2019]:

Substantia nigra: Increased expression in dopaminergic regions[@mcgeer1988]
Microglial activation: Facilitates recruitment of peripheral macrophages[@croisier2005]
BBB permeability: Contributes to blood-brain barrier breakdown[@kortekaas2005]
Disease progression: Levels correlate with Hoehn and Yahr stage[@shi2011]

Multiple Sclerosis (MS)

VCAM1 is central to MS pathogenesis[@cannella1998][@engelhardt2010]:

Leukocyte trafficking: Essential for T cell migration across the BBB[@raine1995]
Lesion formation: High expression in active demyelinating lesions[@sobel1993]
Clinical therapy: Natalizumab blocks VLA-4, preventing VCAM1-mediated adhesion[@polman2006]

Stroke and Ischemic Injury

VCAM1 mediates post-ischemic inflammation[@huang2000][@wang2004]:

Early upregulation: Rapidly induced after cerebral ischemia[@zhang1998]
Reperfusion injury: Mediates secondary inflammatory damage[@petty2009]
Therapeutic potential: Blocking VCAM1 reduces infarct size in animal models[@vemuganti2004]
Angiogenesis: Involved in post-stroke blood vessel repair[@hayashi2006]

Amyotrophic Lateral Sclerosis (ALS)

VCAM1 is elevated in ALS[@zhong2008]:

Motor [cortex](/brain-regions/cortex): Increased expression in motor cortex blood vessels[@kim2016]
Spinal cord: Mediates inflammatory cell infiltration[@rossi2012]
Disease progression: Correlates with rate of functional decline[@fiala2010]

Expression and Regulation

Cellular Expression

Endothelial cells: High expression at cell junctions, especially after activation
Smooth muscle cells: Inducible in pathological states
[Astrocytes](/entities/astrocytes): Induced in reactive astrocytes[@satoh1996]
Macrophages/monocytes: Express VCAM1 in inflamed tissues
Epithelial cells: Variable, inducible expression

Regulatory Mechanisms

[NF-κB](/entities/nf-kb): Primary transcriptional regulator[@dustin1990]
AP-1: Cooperates with NF-κB for maximal induction
Cytokines: TNF-α, IL-1β, IFN-γ strongly induce expression
Shear stress: Mechanical forces modulate expression[@chiu2008]
Oxidized lipids: Increase expression in atherosclerosis[@khan1995]

Therapeutic Targeting

Diagnostic and Prognostic Value

Biomarker Applications

Soluble VCAM1 (sVCAM1): Elevated in AD, PD, MS, stroke[@hartung1995]
Blood/CSF correlation: Indicates CNS vs peripheral inflammation
Disease staging: Higher levels correlate with advanced disease[@shi2011]
Treatment monitoring: Changes reflect therapeutic response[@trojano2003]

Research Applications

VCAM1 imaging: PET ligands for visualizing neuroinflammation
Single-cell analysis: VCAM1 expression in distinct immune populations
Organoid models: BBB models incorporating VCAM1 for drug testing

Background

The study of Vcam1 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

[Osborn L, et al, (1989) (1989)](https://pubmed.ncbi.nlm.nih.gov/2481208/)

[Dustin ML, et al, (1990) (1990)](https://pubmed.ncbi.nlm.nih.gov/2121585/)

[Koning GA, et al, (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19386098/)

[Clements JM, et al, (1994) (1994)](https://pubmed.ncbi.nlm.nih.gov/8006064/)

[Elices MJ, et al, (1990) (1990)](https://pubmed.ncbi.nlm.nih.gov/1689956/)

[Unknown, Muller WA (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/12700378/)

[Mould AP, et al, (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/12446740/)

[Garmy-Susini B, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15937552/)

[Yoshida M, et al, (1996) (1996)](https://pubmed.ncbi.nlm.nih.gov/8626567/)

[Gough PJ, et al, (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9529303/)

[Chiu NN, et al, (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11167004/)

[Wang J, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15893701/)

[Grammas P, et al, (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21827635/)

[Unknown, Iadecola C (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28602638/)

[Unknown, Zlokovic BV (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18504134/)

[Michaud JP, et al, (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23904614/)

[Weller RO, et al, (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19052761/)

[Blair LJ, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32958947/)

[Sweeney MD, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31235858/)

[Zhang Z, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31178866/)

[Chen X, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31064373/)

[McGeer PL, et al, (1988) (1988)](https://pubmed.ncbi.nlm.nih.gov/2839804/)

[Croisier E, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15816838/)

[Kortekaas R, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15639321/)

[Shi M, et al, (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21931625/)

[Cannella B, et al, (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9665969/)

[Engelhardt B, et al, (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20577266/)

[Unknown, Raine CS (1995) (1995)](https://pubmed.ncbi.nlm.nih.gov/7644053/)

[Sobel RA, et al, (1993) (1993)](https://pubmed.ncbi.nlm.nih.gov/8423348/)

[Polman CH, et al, (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16428282/)

[Huang J, et al, (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10864296/)

[Wang Q, et al, (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/14765195/)

[Zhang RL, et al, (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9596474/)

[Petty MA, et al, (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/18992725/)

[Vemuganti R, et al, (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15564593/)

[Hayashi T, et al, (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16421508/)

[Zhong Z, et al, (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18501445/)

[Kim J, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27193190/)

[Rossi D, et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22521928/)

[Fiala M, et al, (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20525206/)

[Satoh J, et al, (1996) (1996)](https://pubmed.ncbi.nlm.nih.gov/8786408/)

[Chiu JJ, et al, (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18340012/)

[Khan BV, et al, (1995) (1995)](https://pubmed.ncbi.nlm.nih.gov/7828286/)

[Rice GP, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15928031/)

[Yednock TA, et al, (1992) (1992)](https://pubmed.ncbi.nlm.nih.gov/1329895/)

[Hartung HP, et al, (1995) (1995)](https://pubmed.ncbi.nlm.nih.gov/7668828/)

[Trojano M, et al, (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/12963769/)

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VCAM1 Protein

VCAM1 Protein

VCAM1 Protein

Introduction

Overview

Protein Information

Domain Structure

Extracellular Domain (20-698 aa)

Transmembrane Domain (699-723 aa)

Cytoplasmic Tail (724-739 aa)

Molecular Function

Receptor Binding

Biological Functions

Post-Translational Modifications

Glycosylation

Proteolytic Processing

Structural Insights

Crystal Structures

Domain Organization

Role in Neurodegenerative Diseases

Alzheimer's Disease (AD)

Parkinson's Disease (PD)

Multiple Sclerosis (MS)

Stroke and Ischemic Injury

Amyotrophic Lateral Sclerosis (ALS)

Expression and Regulation

Cellular Expression

Regulatory Mechanisms

Therapeutic Targeting

Diagnostic and Prognostic Value

Biomarker Applications

Research Applications

See Also

Related Proteins

Related Pathways

Background

External Links

References