SERF, a family of tiny highly conserved, highly charged proteins with enigmatic functions

• Published in: The FEBS journal 2023-09, Vol.290 (17), p.4150-4162
• Main Authors: Sahoo, Bikash R, Bardwell, James C A
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Binding; Huntingtin; Movement disorders; Neurodegenerative diseases; Nucleation; Nucleic acids; Parkinson's disease; Polyglutamine; Proteins; Sequences; Synuclein; Trinucleotide repeat diseases; Zinc finger proteins
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16555

Amyloid formation is a misfolding process that has been linked to age-related diseases, including Alzheimer's and Huntington's. Understanding how cellular factors affect this process in vivo is vital in realizing the dream of controlling this insidious process that robs so many people of their humanity. SERF (Small EDRK Rich Factor) was initially isolated as a factor that accelerated polyglutamine amyloid formation in a C. elegans model. SERF knockouts inhibit amyloid formation of a number of proteins that include huntingtin, α-synuclein, and β-amyloid which are associated with Huntington's, Parkinson's and Alzheimer's disease, respectively, and purified SERF protein speeds their amyloid formation in vitro. SERF proteins are highly conserved, highly charged and conformationally dynamic proteins that form a fuzzy complex with amyloid precursors. They appear to act by specifically accelerating the primary step of amyloid nucleation. Brain-specific SERF knockout mice, though viable, appear to be more prone to deposition of amyloids, and show modified fibril morphology. Whole-body knockouts are perinatally lethal due to an apparently unrelated developmental issue. Recently, it was found that SERF binds RNA and is localized to nucleic acid rich membraneless compartments. SERF-related sequences are commonly found fused to zinc finger sequences. These results point toward a nucleic acid-binding function. How this function relates to their ability to accelerate amyloid formation is currently obscure. In this review, we discuss the possible biological functions of SERF family proteins in the context of their structural fuzziness, modulation of amyloid pathway, nucleic acid binding and their fusion to folded proteins.