CD300A Protein

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CD300A Protein

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CD300A Protein

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">CD300A Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>CMRF35-like molecule 8</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>[CD300A](/genes/cd300a)</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>CMRF-35H, CLM-8, IRC1, IGSF12</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q9UGN4](https://www.uniprot.org/uniprot/Q9UGN4)</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>296 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~33 kDa</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>17q25.1</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cell surface, plasma membrane</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

...

CD300A Protein

Overview

CD300A (also known as CMRF-35H, CLM-8, or IRC1) is an inhibitory immunoreceptor of the CD300 family, encoded by the [CD300A](/genes/cd300a) gene on chromosome 17q25.1. CD300A is a type I transmembrane glycoprotein expressed on myeloid cells — including [microglia](/cell-types/microglia), monocytes, macrophages, and mast cells — as well as subsets of T and B lymphocytes[@clark2009][@borrego2013]. The receptor binds phosphatidylserine (PS) and phosphatidylethanolamine (PE) exposed on the outer leaflet of apoptotic cells, damaged [neurons](/entities/neurons), and extracellular vesicles, delivering immunotyrosine-based inhibitory motif (ITIM)-dependent signals that suppress inflammatory activation[@simhadri2008]. In the central nervous system, CD300A functions as a critical "don't eat me / calm down" signal that restrains microglial activation upon encountering dying neurons, making it highly relevant to [neuroinflammation](/mechanisms/neuroinflammation) in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and other neurodegenerative conditions[@neumann2009].

Protein Information

Structure

CD300A is composed of a single IgV-like extracellular domain, a transmembrane segment, and a cytoplasmic tail containing three immunoreceptor tyrosine-based inhibitory motifs (ITIMs)[@clark2009]. Key structural features:

Extracellular Domain

The IgV-like domain adopts a canonical immunoglobulin fold and contains the lipid-binding site. Structural studies reveal a hydrophobic pocket that accommodates the headgroups of phosphatidylserine and phosphatidylethanolamine. This lipid recognition is calcium-dependent, requiring Ca²⁺ coordination at the binding interface[@simhadri2008][@cannon2008].

Cytoplasmic ITIMs

The three ITIM sequences (consensus YxxL/V) in the cytoplasmic tail are phosphorylated by Src family kinases upon receptor ligation. Phosphorylated ITIMs recruit the SH2-domain phosphatases [SHP-1](/proteins/shp1-protein) and [SHP-2](/proteins/shp2-protein), which dephosphorylate activating signaling intermediates and dampen immune cell responses[@clark2009][@borrego2013].

Normal Function

Inhibition of Myeloid Cell Activation

CD300A serves as a master negative regulator of myeloid cell activation. When [microglia](/cell-types/microglia-neuroinflammation), macrophages, or mast cells encounter phosphatidylserine-exposing targets (apoptotic cells, activated platelets, damaged membranes), CD300A engagement recruits SHP-1/SHP-2 to suppress:

Phagocytosis: Excessive engulfment of cells that may still be viable
Cytokine production: TNF-α, IL-6, IL-1β, and other inflammatory mediators
[Reactive oxygen species](/entities/reactive-oxygen-species) (ROS): NADPH oxidase-dependent superoxide generation
Degranulation: In mast cells and eosinophils[@clark2009][@borrego2013]

Efferocytosis Regulation

During physiological turnover of neurons and glia, apoptotic cells expose PS on their outer leaflet. CD300A recognizes this PS and delivers inhibitory signals that ensure efferocytosis (clearance of dead cells) proceeds in an immunologically silent manner, without triggering inflammatory responses[@simhadri2008][@neumann2009].

Immune Homeostasis

CD300A is part of a broader phospholipid-sensing receptor family (CD300a-f) that collectively monitors membrane lipid composition to distinguish healthy cells from damaged or dying ones. CD300A's inhibitory function counterbalances activating receptors like CD300C and CD300E, maintaining immune equilibrium[@cannon2008].

Role in Neurodegeneration

Microglial Restraint in Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), neurons damaged by [amyloid-β](/proteins/amyloid-beta) toxicity expose PS on their surface before committing to [apoptosis](/entities/apoptosis). CD300A on [microglia](/cell-types/microglia) recognizes this PS and suppresses premature phagocytosis (phagoptosis) of stressed-but-viable neurons. Loss of CD300A function may contribute to excessive microglial engulfment of live neurons observed in AD brain tissue[@neumann2009][@hong2016].

Neuroinflammation Modulation

Chronic [neuroinflammation](/mechanisms/neuroinflammation) is a hallmark of neurodegeneration. CD300A's ITIM-dependent inhibitory signaling opposes the sustained pro-inflammatory activation of microglia driven by damage-associated molecular patterns (DAMPs) including ATP, HMGB1, and aggregated proteins. Reduced CD300A expression or function could release the brakes on microglial inflammation, accelerating neuronal damage in AD and PD[@borrego2013][@heneka2015].

Complement System Interaction

CD300A intersects with complement-mediated synaptic elimination. In AD, complement proteins [C1q](/proteins/c1q-protein) and C3 tag synapses for microglial engulfment. CD300A's inhibitory signaling may counteract excessive complement-driven synapse loss, and its downregulation could facilitate the pathological synaptic stripping observed in early AD[@hong2016].

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), dopaminergic neurons in the [substantia nigra](/brain-regions/substantia-nigra) become increasingly vulnerable to microglial attack. CD300A expression on nigral microglia may decline with aging and disease progression, contributing to the shift from neuroprotective to neurotoxic microglial phenotypes. [Alpha-synuclein](/proteins/alpha-synuclein) aggregates can also alter microglial CD300A expression through TLR2/4-dependent signaling[@heneka2015].

Therapeutic Implications

CD300A represents a potential immunomodulatory target for neurodegeneration:

CD300A agonists: Antibodies or lipid mimetics that activate CD300A could suppress excessive neuroinflammation
PS-liposome delivery: Phosphatidylserine-containing liposomes could engage CD300A to calm microglial activation at sites of neurodegeneration
Biomarker potential: Soluble CD300A shed from activated immune cells may serve as a peripheral biomarker of neuroinflammatory status

External Links

[UniProt: Q9UGN4](https://www.uniprot.org/uniprot/Q9UGN4)
[NCBI Gene: CD300A](https://www.ncbi.nlm.nih.gov/gene/11314)
[GeneCards: CD300A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=CD300A)

References

[Clark GJ, Ju X, Tate C, Hart DNJ, The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions (2009)](https://pubmed.ncbi.nlm.nih.gov/19494812/)

[Borrego F, The CD300 molecules: an emerging family of regulators of the immune system (2013)](https://pubmed.ncbi.nlm.nih.gov/23871645/)

[Simhadri VR, Andersen JF, Bhatt DK, et al, Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells (2008)](https://pubmed.ncbi.nlm.nih.gov/18606998/)

[Neumann H, Kotter MR, Franklin RJM, Debris clearance by microglia: an essential link between degeneration and regeneration (2009)](https://pubmed.ncbi.nlm.nih.gov/18923512/)

[Cannon JP, Haire RN, Magis AT, et al, A bony fish immunological receptor of the NITR multigene family mediates allogeneic recognition (2008)](https://pubmed.ncbi.nlm.nih.gov/18703499/)

[Hong S, Beja-Glasser VF, Bhatt DK, et al, Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016)](https://pubmed.ncbi.nlm.nih.gov/27033/)

[Heneka MT, Carson MJ, El Khoury J, et al, Neuroinflammation in Alzheimer's disease (2015)](https://pubmed.ncbi.nlm.nih.gov/25792098/)

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Related Entities

CD300APROTEIN

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slug	proteins-cd300a-protein
kg_node_id	CD300APROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-17d638a047f3
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-cd300a-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

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Certainty

45%

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CD300A Protein

CD300A Protein

Overview

CD300A Protein

Overview

Protein Information

Structure

Extracellular Domain

Cytoplasmic ITIMs

Normal Function

Inhibition of Myeloid Cell Activation

Efferocytosis Regulation

Immune Homeostasis

Role in Neurodegeneration

Microglial Restraint in Alzheimer's Disease

Neuroinflammation Modulation

Complement System Interaction

Parkinson's Disease

Therapeutic Implications

See Also

External Links

References

💬 Discussion