Two different neurodegenerative diseases caused by proteins with similar structures

Abstract

The downstream prion-like protein (doppel, or Dpl) is a paralog of the cellular prion protein, PrP C . The two proteins have Ϸ25% 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 ␤-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 ␤-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.doppel protein structure ͉ NMR ͉ protein structures ͉ prion protein ͉ prion diseases

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…In fact, Dpl-mediated toxicity of PCs is reversed by the introduction of WT PrP c (Yamaguchi et al, 2004). However, the role of Dpl is not clear since it shows low expression in adult brain and the studies performed to date have focused on its roles during development and in other organs (Behrens and Aguzzi, 2002) and also its functions in prion pathogenesis (Behrens et al, 2001;Mo et al, 2001) Dpl protein shares with PrP c the C-terminal portion of the molecule but lacks the OR and CD, although it conserves the GPI anchor (Moore et al, 1999). On the basis of these observations, several studies were directed to analyzing the phenotype of mice expressing truncated forms of PrP c (lacking some portions of the N-terminal domains).…”

“…However, these studies are subject to debate since the requirement of PrP c expression for synthetic peptide toxicity is controversial (see for example (Brown, 2000;Fioriti et al, 2005;Gavin et al, 2005;Kunz et al, 1999;Singh et al, 2002)). N-terminally truncated constructions, like F35 or Dpl protein, lack residues 105-125 (Luhrs et al, 2003;Mo et al, 2001;Shmerling et al, 1998). F35 and Dpl overexpression promotes neural cell death in several mouse models, thereby implicating the 105-125 region in survival signaling and indicating that its absence promotes the activation of several death-related pathways.…”

Priones y enfermedades espongiformes transmisibles

“…2 El prión PrP Sc se deriva de la isoforma celular benigna PrP C mediante un proceso postranslacional que involucra un cambio profundo en la conformación. 4 Aunque algunos casos de ECJ se deben a mutaciones en el gen que codifica la PrP, es decir, son hereditarios, otros (con muy baja frecuencia) se deben a la transmisión de EEB a humanos por medio del alimento. 2,5 Sin embargo, se piensa que la mayoría de los casos son causa de la generación del prión de novo.…”

“…3 Por ello, se presume que el paso de PrP C a PrP Sc se da por replegamiento dirigido. 4 Es decir, puede haber otra u otras moléculas involucradas en el fenómeno.…”

Molecular biology of prion protein and its first homologous protein

“…The protein structural analysis clearly showed that PrPLP/ Dpl is a structural homologue of the C-terminal globular domain of PrP C , composed of three α-helices and two short antiparallel β-strands ( Fig. 1) (21).…”