Research Update – Bacterial curli protein and amyloid sequences

Last year, PeerJ published “Bacterial curli protein promotes the conversion of PAP248-286 into the amyloid SEVI: cross-seeding of dissimilar amyloid sequences”. Over a year has passed since that publication, and the article has already been cited several times, so we felt it would be informative to ask Ayyalusamy Ramamoorthy—lead author on this publication—to comment on the impact of his work.

PJ: Can you tell us a bit about yourself

imageAR: I am Robert W. Parry collegiate professor of Chemistry and Biophysics at the University of Michigan, Ann Arbor, USA. My research focuses on biophysical and biochemical studies of amyloid proteins and membrane proteins, and also on the development of high-resolution solid-state NMR spectroscopy to study biomacromolecules.

PJ: Can you briefly explain the research you published in PeerJ?

AR: Amyloid aggregates of the fragments of prostatic acid phosphatase (PAP248-286) (called SEVI (Semen Enhancer of Viral Infection)) have been shown to significantly enhance HIV infection. In the study published in PeerJ, we investigated the influence of exogenous factors that could promote SEVI fiber formation in-vivo, since the aggregates of SEVI are formed very slowly in in vitro conditions.  We have shown that a bacterially-produced extracellular amyloid (curli or Csg) acts as a catalytic agent for SEVI formation from PAP248-286 at low concentrations in vitro, producing fibers that retain the ability to enhance HIV infection. Cross-seeding PAP248-286 with curli only moderately affects the nucleation rate while significantly enhancing the growth of fibers from existing nuclei. This pattern is in contrast to most previous observations of cross-seeding, which show cross-seeding partially bypasses the nucleation step but has little effect on fiber elongation. Seeding other amyloidogenic proteins (IAPP(islet amyloid polypeptide) and Aβ1−40) with curli showed varied results. The ability of curli fibers to interact with proteins of dissimilar sequences suggests cross seeding may be a more general phenomenon than previously supposed.

PJ: What was the reception of your peers to this publication, and would you say that this publication has influenced others?

AR: Cross seeding of amyloid formation is an important aspect to be investigated for a variety of amyloid proteins and the implications in amyloid diseases. Under in vivo conditions, interactions between different types of amyloid proteins could influence the properties of an amyloid protein which could play important roles in amyloid diseases.  Our study has changed the way researchers think about amyloid aggregation and the interpretation of in vitro results to better understand amyloid diseases like Alzheimer’s disease and type-2 diabetes. Now, many research groups are investigating synergistic aspects of different types of amyloids like amyloid-beta and amylin (or also known as islet amyloid polypeptide protein), and in some cases to search for amyloid inhibitors for the potential development of drugs to treat amyloid diseases.

PJ: Why do you think it has been highly cited and downloaded?

AR: Investigation of misfolding of amyloid proteins is a very hot area of research and it is also multidisciplinary. Researchers from physics, biophysics, engineering, chemistry, and medicine are engaged in this area of research to address questions related to different aspects of amyloid proteins. Any new findings related to protein misfolding will have a high impact  in these areas. So, our publication has been found to be highly significant and is therefore having an excellent impact in these areas.

Our study has reported a highly significant significant phenomenon and it has a broader impact on other areas of amyloid diseases as well. For example, research focused on the biophysical aspects of protein misfolding and aggregation, development of amyloid inhibitors, biochemical or chemical biology studies of amyloid-induced cell toxicity and other areas in aging related diseases significantly benefit from the findings reported in our publication reported in PeerJ.

PJ: How has your research progressed since the publication?

AR: We are investigating many different aspects of amyloid proteins: high-resolution structural studies of amyloid oligomers, development of amyloid inhibitors, amyloid-membrane interactions, factors influencing cell toxicity, etc. We have also made excellent contributions in the areas of type-2 diabetes and Alzheimer’s disease related amyloid proteins. We have reported high-resolution structures of amyloid-beta and amylin proteins.

We are also investigating synergistic interactions between other amyloid proteins that include amylin (or IAPP) and insulin, amylin and amyloid-beta, and the role of cell membrane. Investigation of the mechanisms of amyloid-induced cell toxicity and the role of molecular crowding are also in progress in my laboratory.

We hope to read more about Prof Ramamoorthy’s research soon, and we encourage any others working in related fields to submit their work to PeerJ.

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