A Bacteriophage Capsid Protein Provides a General Amyloid Interaction Motif (GAIM) That Binds and Remodels Misfolded Protein Assemblies

Krishnan, Rajaraman; Tsubery, Haim; Proschitsky, Ming; Asp, Eva; Lulu, Michal; Gilead, Sharon; Gartner, Myra; Waltho, Jonathan P.; Davis, Peter J.; Hounslow, Andrea M.; Kirschner, Daniel A.; Inouye, Hideyo; Myszka, David G.; Wright, Jason; Solomon, Beka; Fisher, Richard A.

doi:10.1016/j.jmb.2014.04.015

Cited by 56 publications

(52 citation statements)

References 64 publications

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“…However, whether this Aβ-plaque clearance is due to fibril disaggregation (as with select anti-Aβ antibodies that bind the N-terminal region of Aβ [62,63]), phagocytic clearance by microglia, or both is uncertain [61••]. Several other ATP-independent protein disaggregases have emerged including a subunit of the chloroplast signal recognition particle [64–66], cyclophilin [67–69], HtrA1 [70••], and gene 3 protein (g3p) [71••]. …”

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

“…Remarkably, g3p enables M13 bacteriophages to slowly remodel diverse amyloids, including those formed by Aβ42, α-syn, tau, and NM (the prion domain of Sup35) [71••,73]. This amyloid-remodeling activity may enable phages to infect bacteria by penetrating protective amyloid-based biofilms [74].…”

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

“…This amyloid-remodeling activity may enable phages to infect bacteria by penetrating protective amyloid-based biofilms [74]. The amyloid-binding activity of g3p was mapped to its two N-terminal domains, which are separated by a glycine-rich hinge [71••]. A recombinant soluble g3p fragment, termed G3P, which comprises the two N-terminal domains and the hinge could bind diverse amyloids but could not disaggregate them [71••].…”

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

“…The amyloid-binding activity of g3p was mapped to its two N-terminal domains, which are separated by a glycine-rich hinge [71••]. A recombinant soluble g3p fragment, termed G3P, which comprises the two N-terminal domains and the hinge could bind diverse amyloids but could not disaggregate them [71••]. However, 3–5 copies of g3p form an oligomer at the tip of the filamentous phage capsid [72].…”

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

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Designer protein disaggregases to counter neurodegenerative disease

Shorter

2017

Current Opinion in Genetics & Development

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Protein misfolding and aggregation unify several devastating neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. There are no effective therapeutics for these disorders and none that target the reversal of the aberrant protein misfolding and aggregation that cause disease. Here, I showcase important advances to define, engineer, and apply protein disaggregases to mitigate deleterious protein misfolding and counter neurodegeneration. I focus on two exogenous protein disaggregases, Hsp104 from yeast and gene 3 protein from bacteriophages, as well as endogenous human protein disaggregases, including: (a) Hsp110, Hsp70, Hsp40, and small heat-shock proteins; (b) HtrA1; and (c) NMNAT2 and Hsp90. I suggest that protein-disaggregase modalities can be channeled to treat numerous fatal and presently incurable neurodegenerative diseases.

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Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

Section: Gene 3 Protein a Protein Disaggregase From Bacteriophage M13mentioning

confidence: 99%

See 2 more Smart Citations

Designer protein disaggregases to counter neurodegenerative disease

Shorter

2017

Current Opinion in Genetics & Development

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“…This would also eliminate the need for ATP to fuel the conformational switch. Interestingly, the phage protein g3p binds a large number of amyloid proteins in a conformation-dependent manner with very high affinity (Krishnan et al, 2014) ( Figure 2). …”

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confidence: 99%

Remodeling Amyloid Fibers: Baker’s Yeast Shows Us the Way

Asp

Proschitsky

Krishnan

2015

Chemistry & Biology

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Proteopathies are a large and diverse group of human diseases that are caused by protein misfolding. Well-known examples of proteopathies are Alzheimer's and Parkinson's disease, which are both linked to amyloid fibril formation. In this issue of Chemistry & Biology, Castellano et al. (2015) describe the way to harness the power of a protein from baker's yeast, Hsp104, to disaggregate the fibrils.

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