9qyn | pdb_00009qyn
Alpha-synuclein K21A fibril type 1A polymorph in the presence of ATP
Structural highlights
DiseaseSYUA_HUMAN Note=Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1. Defects in SNCA are the cause of Parkinson disease type 1 (PARK1) [MIM:168601. A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early-onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features.[1] [2] [3] Defects in SNCA are the cause of Parkinson disease type 4 (PARK4) [MIM:605543. A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. Defects in SNCA are the cause of dementia Lewy body (DLB) [MIM:127750. A neurodegenerative disorder clinically characterized by mental impairment leading to dementia, parkinsonism, often with fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease. FunctionSYUA_HUMAN May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation. Publication Abstract from PubMedPathological amyloids, like those formed by alpha-synuclein in Parkinson's disease, are recently found to catalyze the hydrolysis of model substrates in vitro. Here it is reported that the universal energy molecule ATP is another substrate for alpha-synuclein amyloid chemical catalysis. To reveal the underlying mechanism, the high-resolution cryo-EM structure of the amyloids in the presence of ATP is solved. The structure reveals a type 1A amyloid fold with an additional beta-strand involving residues 16-22 that wraps around the ATP, creating an enclosed cavity at the interface of the protofilaments. Mutations of putative ATP-interacting residues in the cavity and the additional beta-strand showed that replacing any one of Lys21, Lys23, Lys43, Lys45, and Lys60 with Ala reduced amyloid-mediated ATPase activity. High-resolution structural analysis of Lys21Ala alpha-synuclein amyloids in the presence of ATP reveals the same fold as wild-type alpha-synuclein amyloids but without the extra beta-strand and with ATP oriented differently. It is concluded that positively-charged side chains, along with ordering of the N-terminal part into a beta-strand, enclosing the cavity, are essential parameters governing ATP hydrolysis by alpha-synuclein amyloids. Amyloid-catalyzed ATP hydrolysis may hamper ATP-dependent rescue systems near amyloid deposits in vivo. ATP Hydrolysis by alpha-Synuclein Amyloids is Mediated by Enclosing beta-Strand.,Frey L, Buratti FA, Horvath I, Parate S, Kumar R, Riek R, Wittung-Stafshede P Adv Sci (Weinh). 2025 Oct 16:e08441. doi: 10.1002/advs.202508441. PMID:41099718[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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