SORT1 Protein (Sortilin 1)

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SORT1 Protein (Sortilin 1)

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SORT1 Protein (Sortilin 1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">SORT1 (Sortilin 1)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[SORT1](/genes/sort1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q99549" target="_blank">Q99549</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/4J0X" target="_blank">4J0X</a></td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>110 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Plasma membrane, Golgi apparatus, endosomes</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Vps10p-domain receptor family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Cardiovascular Disease](/diseases/cvd)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">19 edges</a></td>
</tr>
</table>

Introduction

...

SORT1 Protein (Sortilin 1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">SORT1 (Sortilin 1)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[SORT1](/genes/sort1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q99549" target="_blank">Q99549</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/4J0X" target="_blank">4J0X</a></td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>110 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Plasma membrane, Golgi apparatus, endosomes</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Vps10p-domain receptor family</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Cardiovascular Disease](/diseases/cvd)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">19 edges</a></td>
</tr>
</table>

Introduction

SORT1 (Sortilin 1) is a member of the Vps10p-domain receptor family that functions as a pivotal sorting receptor for various ligands, including [ApoE](/proteins/apoe-protein), lipoprotein lipase, and neurotensin[@rogaeva2007][@carlo2013]. In the brain, SORT1 plays critical roles in lipid metabolism, protein trafficking, and has been genetically implicated in [Alzheimer's disease](/diseases/alzheimers-disease) risk through genome-wide association studies.

Structure

SORT1 is a type I transmembrane protein with a complex multi-domain architecture[@jacquemet2015]:

Extracellular Domains

Vps10p domain: Large extracellular domain (residues 45-780) that binds diverse ligands
10 CC (cysteine-rich complement) repeats: Ligand-binding diversification
Trimerization interface: Forms functional complexes on cell surface

Transmembrane Region

Single pass transmembrane helix: Anchors receptor in membrane
Dimerization motif: Facilitates receptor dimerization

Cytoplasmic Tail

Sorting motifs: Contains NPF and dileucine motifs for intracellular trafficking
Tyrosine-based signals: Direct endocytosis and lysosomal targeting
PDZ binding motif: Interacts with PDZ domain proteins

Normal Physiological Function

Protein Sorting

SORT1 functions as a master sorting receptor in the secretory and endocytic pathways[@rogaeva2007][@willnow2012]:

Lipoprotein trafficking: Regulates secretion and internalization of lipoproteins
Receptor trafficking: Controls surface expression of various receptors
Endosomal sorting: Directs proteins to lysosomes or back to plasma membrane
Golgi function: Mediates protein sorting at the trans-Golgi network

Brain Functions

In the central nervous system, SORT1 has several critical roles[@lane2013]:

ApoE metabolism: Primary receptor for ApoE uptake in [neurons](/entities/neurons) and glia
Lipid homeostasis: Regulates brain cholesterol and phospholipid distribution
Neurotrophin trafficking: Modulates neurotrophin receptor (p75NTR) trafficking
Synaptic function: Involved in synaptic vesicle protein sorting

Peripheral Functions

Hepatic lipid metabolism: Major determinant of plasma LDL levels
Adipocyte function: Regulates lipoprotein lipase storage and release
Muscle metabolism: Influences triglyceride uptake

Role in Alzheimer's Disease

Genetic Evidence

GWAS have identified SORT1 variants associated with AD risk[@leduc2015][@zhou2015]:

Chromosome 1p13 locus: rs629185 increases AD risk (~10-15% per allele)
Expression regulation: Risk alleles associated with increased SORT1 expression
Pleiotropy: Also associated with plasma LDL cholesterol

Pathogenic Mechanisms

SORT1 contributes to AD through multiple interconnected mechanisms[@malmquist2016]:

ApoE Dysregulation

Altered ApoE trafficking: Risk variants affect ApoE brain distribution
ApoE4 interaction: Particularly significant in APOE4 carriers
Lipidation state: Affects ApoE lipidation and function

Amyloid Metabolism

APP processing: Modulates [amyloid precursor protein](/entities/app-protein) trafficking
[Aβ](/proteins/amyloid-beta) clearance: Influences Aβ uptake by neurons and glia
BACE1 trafficking: May affect [beta-secretase](/entities/bace1) localization

Lipid Dyshomeostasis

Brain cholesterol: Alters neuronal cholesterol homeostasis
Lipid raft composition: Affects membrane microdomain function
Synaptic lipids: Impairs synaptic maintenance and function

Therapeutic Implications

SORT1 represents a promising therapeutic target[@huang2019]:

Small molecule inhibitors: Block SORT1-ApoE interaction
Antisense oligonucleotides: Reduce SORT1 expression
Antibody therapy: Neutralize SORT1 in brain
Gene therapy: Modulate SORT1 expression

Key Publications

[Rogaeva, E. et al. (2007) SORT1 variants in AD (Nature Genetics)](https://doi.org/10.1038/ng.2007.50)

[Carlo, A.S. et al. (2013) Sortilin and ApoE in the brain (Neuron)](https://doi.org/10.1016/j.neuron.2013.07.004)

[Thinnes, F.P. et al. (2014) SORT1 structure and function (Cellular and Molecular Life Sciences)](https://doi.org/10.1007/s00018-014-1593-4)

[Lane, R.F. et al. (2013) SORT1 and amyloid metabolism (Journal of Neuroscience)](https://doi.org/10.1523/JNEUROSCI.1544-13.2013)

Cross-References

[SORT1 Gene](/genes/sort1) — Gene encoding SORT1
[ApoE Protein](/proteins/apoe-protein) — Key interacting protein
[Alzheimer's Disease](/diseases/alzheimers-disease) — Primary disease
[Lipid Metabolism](/mechanisms/lipid-metabolism-alzheimers) — Lipid pathway
[APOE Gene](/genes/apoe) — [Apolipoprotein E](/proteins/apoe) gene
[VLDLR](/proteins/vldlr-protein) — Related lipoprotein receptor

External Links

[UniProt: Q99549](https://www.uniprot.org/uniprot/Q99549)
[PDB: 4J0X](https://www.rcsb.org/structure/4J0X)
[OMIM: 602560](https://www.omim.org/entry/602560)
[PDGene: SORT1](https://www.pdgene.org/)

References

[Rogaeva, E. et al, SORT1 variants and Alzheimer's disease risk (2007)](https://doi.org/10.1038/ng.2007.50)

[Carlo, A.S. et al, Sortilin is essential for ApoE metabolism in the brain (2013)](https://doi.org/10.1016/j.neuron.2013.07.004)

[Jacquemet, G. et al, The Vps10p-domain receptor family (2015)](https://doi.org/10.1016/j.tcb.2015.05.004)

[Willnow, T.E. et al, Sortilin and lipid metabolism (2012)](https://doi.org/10.1016/j.tcm.2012.03.005)

[Lane, R.F. et al, Sortilin modulates amyloid-beta metabolism (2013)](https://doi.org/10.1523/JNEUROSCI.1544-13.2013)

[Leduc, V. et al, SORT1 and lipid homeostasis in AD (2015)](https://doi.org/10.1016/j.neurobiolaging.2015.04.017)

[Zhou, L. et al, Genetic architecture of SORT1 in AD risk (2015)](https://doi.org/10.1093/brain/awv059)

[Malmquist, K. et al, Sortilin in neurodegenerative diseases (2016)](https://doi.org/10.3233/JAD-160060)

[Huang, T.Y. & Bohnen, S, Targeting SORT1 for AD therapy (2019)](https://doi.org/10.1186/s13195-019-0530-z)

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Related Entities

SORT1PROTEIN

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kg_node_id	SORT1PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5eb693bb8b0f
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-sort1-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

200

Outgoing

212

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SORT1 Protein (Sortilin 1)

SORT1 Protein (Sortilin 1)

Introduction

SORT1 Protein (Sortilin 1)

Introduction

Structure

Extracellular Domains

Transmembrane Region

Cytoplasmic Tail

Normal Physiological Function

Protein Sorting

Brain Functions

Peripheral Functions

Role in Alzheimer's Disease

Genetic Evidence

Pathogenic Mechanisms

ApoE Dysregulation

Amyloid Metabolism

Lipid Dyshomeostasis

Therapeutic Implications

Key Publications

Cross-References

See Also

External Links

References

💬 Discussion