Two different neurodegenerative diseases caused by proteins with similar structures.
The downstream prion-like protein (doppel, or Dpl) is a paralog of the cellular prion protein, PrP(C). The two proteins have approximately 25% sequence identity, but seem to have distinct physiologic roles. Unlike PrP(C), Dpl does not support prion replication; instead, overexpression of Dpl in the brain seems to cause a completely different neurodegenerative disease. We report the solution structure of a fragment of recombinant mouse Dpl (residues 26-157) containing a globular domain with three helices and a small amount of beta-structure. Overall, the topology of Dpl is very similar to that of PrP(C). Significant differences include a marked kink in one of the helices in Dpl, and a different orientation of the two short beta-strands. Although the two proteins most likely arose through duplication of a single ancestral gene, the relationship is now so distant that only the structures retain similarity; the functions have diversified along with the sequence.
Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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H
Mo
R C
RC
Moore
F E
FE
Cohen
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D
Westaway
S B
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Prusiner
P E
PE
Wright
H J
HJ
Dyson
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D004220:Disulfides / Q000737:chemistry; D058851:GPI-Linked Proteins; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D018621:PrPC Proteins / Q000737:chemistry / Q000502:physiology*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D004220:Disulfides; D058851:GPI-Linked Proteins; C501125:PRND protein, human; D018621:PrPC Proteins; D011328:Prions; D011994:Recombinant Proteins