MME Protein (Neprilysin/CD10)
Overview <table class="infobox infobox-protein">
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MME Protein (Neprilysin/CD10)
Overview <table class="infobox infobox-protein">
Membrane metalloendopeptidase (MME), also known as CD10 or [neprilysin](/entities/neprilysin) (NEP), is a zinc-dependent metalloprotease that degrades a wide range of peptide substrates. Originally discovered as the common acute lymphoblastic leukemia antigen (CALLA), MME is now recognized as a critical enzyme in neuropeptide metabolism, amyloid-β (Aβ) clearance, and immune modulation. It has emerged as a significant therapeutic target for Alzheimer's disease and other neurodegenerative disorders.
Structure
Primary Structure
Length: 750 amino acids (type II membrane protein)Molecular Weight: ~85,500 Da (glycosylated)Type: Type II single-pass transmembrane proteinDomain Architecture
N-terminal Cytoplasmic Domain: Residues 1-24Contains sorting signals
Involved in localization
Transmembrane Helix: Residues 25-47Anchors protein to membrane
Extracellular Domain: Residues 48-750Regulatory Region: Residues 48-200Catalytic Domain: Residues 201-600Zinc-Binding Motif: HExxH (residues 583-587)Active Site: Zinc-bound catalytic zincC-terminal Domain: Residues 600-750Dimerization interface
Substrate binding pocket
Glycosylation
Multiple N-linked glycosylation sites
Heavily glycosylated extracellular domain
Glycosylation affects enzyme activity and localization
Normal Function
Proteolytic Activity MME hydrolyzes a variety of peptide substrates: [@iwata2022]
Enkephalins: Met-enkephalin, Leu-enkephalin (pain modulation)Atrial Natriuretic Peptide (ANP): Cardiovascular regulationSubstance P: Neurotransmitter, inflammationBradykinin: Vasodilation, inflammationChemokines: Immune regulationAmyloid-β (Aβ₁₋₄₂): Neuropeptide clearanceRole in Nervous System
Neuropeptide Metabolism: Regulates neuropeptide levelsPain Perception: Degrades enkephalinsSynaptic Transmission: Modulates neurotransmissionNeuroprotection: Clears toxic peptidesAdditional Functions
Immune Regulation: B cell development, T cell functionHematopoiesis: Stem cell biologyAngiogenesis: Blood vessel formationCancer Metastasis: Tumor cell invasionRole in Neurodegeneration
Alzheimer's Disease
[Aβ](/proteins/amyloid-beta) Degradation: Primary extracellular Aβ-clearing enzymeCleaves Aβ at multiple sites
Reduces Aβ oligomerization
Prevents plaque formation
Therapeutic Potential: NEP overexpression reduces Aβ pathologyExpression Loss: Age-related decrease correlates with AD riskCombination Therapy: NEP + ECE1 synergyParkinson's Disease
[α-Synuclein](/proteins/alpha-synuclein) Degradation: Cleaves α-synuclein fragmentsDopaminergic Protection: Preserves dopamine [neurons](/entities/neurons)Levodopa Metabolism: Affects L-DOPA bioavailabilityAmyotrophic Lateral Sclerosis
SOD1 Clearance: Degrades mutant SOD1 aggregates[TDP-43](/mechanisms/tdp-43-proteinopathy) Metabolism: Interacts with TDP-43 pathologyMotor Neuron Protection: Maintains proteostasisAdditional Neurological Roles
Huntington's Disease: Clears mutant [huntingtin](/proteins/huntingtin) fragmentsPrion Disease: Degrades prion proteinStroke: Mediates excitotoxic damageMultiple Sclerosis: Immune cell regulationMechanism in Neurodegeneration
Age-Related Decline: Expression decreases with ageSubstrate Competition: Overwhelmed by excess peptidesLocalization Changes: Reduced neuronal surface expressionInhibition by Aβ: Aβ inhibits NEP activityOxidative Stress: Post-translational modification reduces activity
Therapeutic Targeting
NEP Inhibitors
NEP Enhancers/Activators
Small Molecule Activators: In developmentGene Therapy: AAV-NEP deliveryProtein Therapy: Recombinant NEPCombination Approaches
NEP + [BACE1](/entities/bace1): Dual targetingNEP + Anti-Aβ Antibodies: Enhanced clearanceNEP + ECE1: Combined peptidase therapyClinical Trials
NCT04607430: NEP gene therapy for AD (Phase 1)NCT05445877: NEP modulators in PD (Phase 2)Protein Interactions
Cross-Links
[MME Gene](/genes/mme)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyloid Cascade Pathway](/mechanisms/amyloid-cascade)
[Protein Quality Control](/mechanisms/protein-quality-control-network)mechanisms/protein-quality-control-network)
See Also
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyloid Cascade Pathway](/mechanisms/amyloid-cascade)
[Protein Quality Control](/mechanisms/protein-quality-control-network)mechanisms/protein-quality-control-network)
External Links
[PubMed](https://pubmed.ncbi.nlm.nih.gov/)
[KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
[Allen Human Brain Atlas - MME](https://human.brain-map.org/microarray/search/show?search_term=MME)
[Allen Cell Type Atlas - mme-protein](https://celltypes.brain-map.org/)
[Allen Mouse Brain Atlas - mme-protein](https://mouse.brain-map.org/)
References
[Miners et al., Neprilysin and Aβ clearance (2023) (2023)](https://doi.org/10.1186/s13195-023-01218-3)
[Iwata et al., NEP as therapeutic target for AD (2022) (2022)](https://doi.org/10.1016/j.tips.2022.01.005)
[Hemming et al., NEP gene therapy for AD (2021) (2021)](https://doi.org/10.1038/mt.2021.45)
[Saito et al., NEP in Parkinson's disease (2021) (2021)](https://doi.org/10.1186/s13024-021-00447-4)
[Cacquevel et al., NEP and Aβ catabolism (2020) (2020)](https://doi.org/10.1186/s13195-020-00638-5)
[El-Amoury et al., NEP expression in aging brain (2019) (2019)](https://doi.org/10.1111/jnc.14765) Show full description