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

Abstract

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 towards 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.

Visualizing liquid-liquid phase transitions

“…As an emerging cellular component, [9][10][11][12][13] rG4 quadruplexes may function as translational repressors and transcriptional regulators, as well as being involved with mRNA processing, mRNA polyadenylation and splicing, telomere maintenance, and RNA translocation, 3,10,14,16,47,[71][72][73][74] although their mechanism of action remains unclear. 36,75 In findings likely relevant to ours, it had recently been found that stress enhances the amount of rG4 quadruplexes present, 4 rG4 quadruplexes are abundant in stress granules, stress promotes rG4 quadruplex folding 4 and RNA quadruplexes may facilitate the formation of stress granules. 5,76 A handful of RNA binding proteins, such as FMRP, nucleolin, CNBP, eIF4A, hnRNPA1, and DHX36, have been shown to bind rG4 quadruplexes, and modulate their folding.…”

“…SERF proteins were initially identified as a driver of amyloid formation, a process that has been linked to a number of age related diseases, 33–36 but their normal physiological functions remain obscure. 36 SERF proteins are remarkably small, averaging about ∼70 amino acids in length, and they share a conserved, highly charged N-terminal domain.…”

“…36 SERF proteins are remarkably small, averaging about ∼70 amino acids in length, and they share a conserved, highly charged N-terminal domain. 36 Here, we present evidence that SERF2 facilitates stress granule formation through its ability to interact with rG4 quadruplexes, colocalizes with rG4 quadruplexes and stress granule marker proteins such as FUS and G3BP1. Multiple structural restraints were used to generate a high-resolution structural ensemble of SERF2 and SERF2-rG4 quadruplex complex that gives us a glimpse into the initial stages of liquid-liquid phase transition.…”

New Specific α‐Glucosidase Inhibitor Flavonoid from Thymelaea tartonraira Leaves: Structure Elucidation, Biological and Molecular Docking Studies

“…A π‐π stacked interaction was also established between the unsaturated ring B and the amino acid Tyr62 at the distance of 4.12 Å. This compound showed a similar binding pattern as observed for reference inhibitor acarbose such as Val 163 and most importantly the polar interaction with the catalytic amino acid Asp 300 [34,35] …”

“…This compound showed a similar binding pattern as observed for reference inhibitor acarbose such as Val 163 and most importantly the polar interaction with the catalytic amino acid Asp 300. [34,35] In the compound 4/α-glucosidase complex (Figure 6 C and D), many intermolecular interactions are established between the docked molecule and the active amino acids of α-glucosidase including conventional hydrogen bonds, carbon hydrogen bonds, π-π T-shaped and π-π stacked interactions. Five hydrogen bonds are formed in the C4/α-glucosidase complex.…”