9FOR

Structure of heteromeric amyloid filament of TDP-43 and AXNA11 from FTLD-TDP Type C (variant 1)

Summary for 9FOR

• Entry DOI: 10.2210/pdb9for/pdb
• EMDB information: 50628
• Descriptor: TAR DNA-binding protein 43, Annexin A11 (2 entities in total)
• Functional Keywords: tdp-43, anxa11, amyloid, heteromeric amyloid, ftld-tdp, ftld-tdp type c, neurodegeneration, neurodegenerative disease, dementia, brain, protein fibril, filament
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 49163.97

Authors

Arseni, D.,Ryskeldi-Falcon, B. (deposition date: 2024-06-12, release date: 2024-07-24, Last modification date: 2024-10-23)

Primary citation

Arseni, D.,Nonaka, T.,Jacobsen, M.H.,Murzin, A.G.,Cracco, L.,Peak-Chew, S.Y.,Garringer, H.J.,Kawakami, I.,Suzuki, H.,Onaya, M.,Saito, Y.,Murayama, S.,Geula, C.,Vidal, R.,Newell, K.L.,Mesulam, M.,Ghetti, B.,Hasegawa, M.,Ryskeldi-Falcon, B.
Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C.
Biorxiv, 2024

PubMed Abstract: Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system . Human genetic studies established a causal role for protein assembly in neurodegeneration . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains . All diseases studied to date have been characterised by the self-assembly of a single intracellular protein in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) Types A and B . Here, we used cryo-EM to determine filament structures from the brains of individuals with FTLD-TDP Type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/284-N345 and ANXA11 residues L39-L74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 previously implicated in protein-protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as a ∼22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections confirmed the co-localisation of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP Type C. This work establishes a central role for ANXA11 in FTLD-TDP Type C. The unprecedented formation of heteromeric amyloid filaments in human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.

PubMed: 38979278
DOI: 10.1101/2024.06.25.600403

Experimental method

ELECTRON MICROSCOPY (2.75 Å)