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.
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H
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Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Moore
R C
RC
Cohen
F E
FE
Westaway
D
D
Prusiner
S B
SB
Wright
P E
PE
Dyson
H J
HJ
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