Identification of the poly-L-proline-binding site on human profilin.

Metzler, William J.; Bell, Aneka; Ernst, Eileen; Lavoie, Thomas B.; Mueller, Luciano

doi:10.1016/s0021-9258(17)41821-7

Cited by 104 publications

(38 citation statements)

References 37 publications

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“…11 ABC ) seen for residues 86-93. Although more weakly than long stretches of pure polyproline [34][35], a synthetic peptide corresponding to residues P166-P175 of hCPEB3 binds to human Profilin 1, a known mediator of interactions with actin ( Sup. Fig.…”

Section: Resultsmentioning

confidence: 99%

Preferred conformations in the disordered region of human CPEB3, a functional amyloid linked to memory consolidation

Mingo

Pantoja-Uceda

Hervás

et al. 2020

Preprint

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Highlights:· Human CPEB3's aggregation-prone disordered region is studied by NMR. · In the monomeric state, the polyQ stretch is disordered and flexible. · 5 a-helices, 2 PPII helices and a rigid nonpolar stretch are identified. · Association of the first 4 a-helices could promote functional amyloid formation. · The PPII helices could negatively regulate this process. · The last a-helix forms the NES and putatively regulates nucleocytoplasmic transport via STAT5B. AbstractAmyloids play key pathological roles in a score of neurodegenerative diseases, but they are also essential to several physiological processes. Perhaps the most fascinating functional amyloid is formed by the Cytoplasmic Polyadenylation Element Binding protein (CPEB) protein family as its structural conversion is essential for memory consolidation in different animals. In vitro, CPEB amyloid formation is driven by the intrinsically disordered region (IDR) present in neuronal-specific isoforms. However, the underlying conformational transitions from the monomeric state to the amyloid state remain poorly understood. Here, we characterize the residue level conformational preferences and ps-ns dynamics for human CPEB3 (hCPEB3) by high field, heteronuclear NMR spectroscopy. At 426 residues, this is the second longest IDR characterized to date in such detail.We find that the residues 1-29: M1QDDLLMDKSKTQPQPQQQQRQQQQQPQP29, adopt an a-helical+disordered Qrich motif. Similar helix + Q/N-rich motifs are observed in CPEB homologs as well as other RNA-binding proteins like TDP-43 that form pathological amyloids. Residues 86-93: P83QQPPPP93, and residues 166-175: P166PPPAPAPQP175 form polyproline-II (PPII) helices, and we propose NMR chemical shift-based criteria for identifying this conformation. We advance that the presence of helix and amyloid breaker residues, such as proline, in hCPEB3 and its absence in TDP-43 may be a key difference between the functional and pathological amyloids in higher eukaryotes. While the (VG)5 repeat motif (residues 272-282) appears to be completely disordered, residues S221-A235 form a highly populated, rather rigid a-helix and two nearby segments adopt partially populated a-helices. Residues 345-355 also form a partially populated a-helix. These residues comprise the nuclear export signal and border a putative phosphoTyr site which may mediate STAT5B binding. Thus, nascent hCPEB3 protein is not fully disordered like a blank sheet of paper; instead, it contains creases which guide the engraving of our memories. Based on these findings and previous results, a working model for hCPEB3 structural transitions in human memory consolidation is advanced.

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Section: Resultsmentioning

confidence: 99%

Preferred conformations in the disordered region of human CPEB3, a functional amyloid linked to memory consolidation

Mingo

Pantoja-Uceda

Hervás

et al. 2020

Preprint

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“…464,465 Besides serving as an essential component of the cytoskeletal rearrangement signaling pathway, PFN1 can interact with a large cohort of proteins with poly-l-proline stretches. 466,467 Curiously, only mutant forms of PFN1 are engaged in the formation of insoluble aggregates, disrupt cytoskeletal structure, inhibit filamentous actin formation, and elevate UBC (ubiquitin C) and SQSTM1/p62 (sequestosome 1) levels in motor neurons, whereas the wild-type protein does not have such activities. 468 It was shown recently that the native conformation of PFN1 in vitro is severely destabilized by the ALS-linked mutations, and the turnover of the PFN1 mutant forms is dramatically accelerated in cells.…”

Section: Normal and Pathological Functions Of Pfn1mentioning

confidence: 99%

The roles of intrinsic disorder-based liquid-liquid phase transitions in the “Dr. Jekyll–Mr. Hyde” behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Uversky

2017

Autophagy

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Pathological developments leading to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are associated with misbehavior of several key proteins, such as SOD1 (superoxide dismutase 1), TARDBP/TDP-43, FUS, C9orf72, and dipeptide repeat proteins generated as a result of the translation of the intronic hexanucleotide expansions in the C9orf72 gene, PFN1 (profilin 1), GLE1 (GLE1, RNA export mediator), PURA (purine rich element binding protein A), FLCN (folliculin), RBM45 (RNA binding motif protein 45), SS18L1/CREST, HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), ATXN2 (ataxin 2), MAPT (microtubule associated protein tau), and TIA1 (TIA1 cytotoxic granule associated RNA binding protein). Although these proteins are structurally and functionally different and have rather different pathological functions, they all possess some levels of intrinsic disorder and are either directly engaged in or are at least related to the physiological liquid-liquid phase transitions (LLPTs) leading to the formation of various proteinaceous membrane-less organelles (PMLOs), both normal and pathological. This review describes the normal and pathological functions of these ALS- and FTLD-related proteins, describes their major structural properties, glances at their intrinsic disorder status, and analyzes the involvement of these proteins in the formation of normal and pathological PMLOs, with the ultimate goal of better understanding the roles of LLPTs and intrinsic disorder in the "Dr. Jekyll-Mr. Hyde" behavior of those proteins.

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“…Of the 18 residues conserved amongst 80 % of profilins, nearly half (Trp3, Tyr6, Ile21, Gly23, Trp31, Ala32, Tyr133 [His133 in bovine profilin] and Leu134) are found in a hydrophobic patch on the surface of profilin distinct from the actin-binding site [11]. This hydrophobic patch has been determined to be responsible for PLP-binding by mutagenesis [35,36], NMR spectroscopy [37,38], and fluorescence quenching [38,39]. Except for the putative , where the average < I > is taken over all equivalent measurements, I hkl , and F P and F PH refer to the native protein structure factor and the protein heavy-atom structure factor, respectively.…”

Section: A Plant-specific Binding Pocketmentioning

confidence: 99%

The crystal structure of a major allergen from plants

et al. 1997

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Comparison of the structures of SH3 domains with those of profilins from three distinct sources suggests that the mode of PLP binding may be similar. A comparison of three profilin structures from different families reveals only partial conservation of the actin-binding surface. The proximity of the semi-conserved actin-binding site and the binding pocket characteristic of plant profilins suggests that epitopes encompassing both features are responsible for the cross-reactivity of antibodies between human and plant profilins thought to be responsible for type I allergies.

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Identification of the poly-L-proline-binding site on human profilin.

Cited by 104 publications

References 37 publications

Preferred conformations in the disordered region of human CPEB3, a functional amyloid linked to memory consolidation

Preferred conformations in the disordered region of human CPEB3, a functional amyloid linked to memory consolidation

The roles of intrinsic disorder-based liquid-liquid phase transitions in the “Dr. Jekyll–Mr. Hyde” behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

The crystal structure of a major allergen from plants

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