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Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-2(1) screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding. | Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-2(1) screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding. | ||
Cryo-EM Structure of the Full-length hnRNPA1 Amyloid Fibril.,Sharma K, Banerjee S, Savran D, Rajes C, Wiese S, Girdhar A, Schwierz N, Lee C, Shorter J, Schmidt M, Guo L, Fandrich M J Mol Biol. 2023 | Cryo-EM Structure of the Full-length hnRNPA1 Amyloid Fibril.,Sharma K, Banerjee S, Savran D, Rajes C, Wiese S, Girdhar A, Schwierz N, Lee C, Shorter J, Schmidt M, Guo L, Fandrich M J Mol Biol. 2023 Sep 15;435(18):168211. doi: 10.1016/j.jmb.2023.168211. Epub 2023 , Jul 20. PMID:37481159<ref>PMID:37481159</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 7zj2" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7zj2" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Nucleoprotein 3D structures|Nucleoprotein 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
Latest revision as of 09:41, 24 July 2024
Amyloid fibril (in vitro) from full-length hnRNPA1 proteinAmyloid fibril (in vitro) from full-length hnRNPA1 protein
Structural highlights
DiseaseROA1_HUMAN Amyotrophic lateral sclerosis;Inclusion body myopathy with Paget disease of bone and frontotemporal dementia. The disease is caused by mutations affecting the gene represented in this entry.[1] The disease is caused by mutations affecting the gene represented in this entry.[2] FunctionROA1_HUMAN Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and may modulate splice site selection. May play a role in HCV RNA replication.[3] Publication Abstract from PubMedHeterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-2(1) screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding. Cryo-EM Structure of the Full-length hnRNPA1 Amyloid Fibril.,Sharma K, Banerjee S, Savran D, Rajes C, Wiese S, Girdhar A, Schwierz N, Lee C, Shorter J, Schmidt M, Guo L, Fandrich M J Mol Biol. 2023 Sep 15;435(18):168211. doi: 10.1016/j.jmb.2023.168211. Epub 2023 , Jul 20. PMID:37481159[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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