Mapping the Fibril Core of the Prion Subdomain of the Mammalian CPEB3 that is Involved in Long Term Memory Retention

Reselammal, Dhanya S.; Pinhero, Faina; Sharma, R. N.; Hassan, Muhammed Shafeek Oliyantakath; Srinivasula, Srinivasa M.; Vijayan, Vinesh

doi:10.1016/j.jmb.2021.167084

Cited by 5 publications

(11 citation statements)

References 60 publications

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“…A construct spanning residues 1-200 of hCPEB3, which contains the Q 4 RQ 4 motif, plays a role in hCPEB3 amyloid formation as indirectly evidenced by the anti-amyloid action of the polyglutamine binding peptide 1 (QBP1) [22] . In the case of the hydrophobic segment, its role in mouse CPEB3 amyloidogenesis has recently been thoroughly corroborated [32]. In addition, the poly-A segment of helices 202-212 and 222-234 may also transform into amyloid ( Figure 5C ).…”

Section: Discussionmentioning

confidence: 85%

“…12) . This finding is interesting considering that this relatively hydrophobic segment also appears to be essential for hCPEB3 amyloid formation in vitro [22] and very recently it has been reported to form amyloid in mouse CPEB3 [32]. In addition, the stretch of residues 161-190: Q 161 HHQQPPPPA 170 PAPQPAQPAQ 180 PPQAQPPQQR 190 , has a very high Q/P content and Pro and Gln are the residues with the highest intrinsic tendencies to adopt PPII helices [33].…”

Section: Resultsmentioning

confidence: 99%

“…recently it has been reported to form amyloid in mouse CPEB3 [32]. In addition, the stretch of residues 161-190: Q161HHQQPPPPA170PAPQPAQPAQ180PPQAQPPQQR190, has a very high Q/P content and Pro and Gln are the residues with the highest intrinsic tendencies to adopt PPII helices [33].…”

Section: Atomic Level Characterization Reveals Partially Structured E...mentioning

confidence: 97%

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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: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

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

Mingo

Pantoja-Uceda

Hervás

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…S 12 ). This finding is interesting considering that this relatively hydrophobic segment also appears to be essential for hCPEB3 amyloid formation in vitro [ 24 ], and very recently, it has been reported to form amyloid in mouse CPEB3 [ 37 ]. In addition, the stretch of residues 161–190 Q 161 HHQQPPPPA 170 PAPQPAQPAQ 180 PPQAQPPQQR 190 has a very high Q/P content, and Pro and Gln are the residues with the highest intrinsic tendencies to adopt PPII helices [ 38 ].…”

Section: Resultsmentioning

confidence: 97%

“…A construct spanning residues 1–200 of hCPEB3, which contains the Q 4 RQ 4 motif, plays a role in hCPEB3 amyloid formation as indirectly inferred by the anti-amyloid action of QBP1 [ 24 ]. For the hydrophobic segment, its role in mouse CPEB3 amyloidogenesis has recently been corroborated [ 37 ]. In addition, the poly-A segment of helices 202–212 and 222–234 may also transform into amyloid (Fig.…”

Section: Discussionmentioning

confidence: 99%

Conformational dynamics in the disordered region of human CPEB3 linked to memory consolidation

et al. 2022

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Background Current understanding of the molecular basis of memory consolidation points to an important function of amyloid formation by neuronal-specific isoforms of the cytoplasmic polyadenylation element binding (CPEB) protein family. In particular, CPEB is thought to promote memory persistence through formation of self-sustaining prion-like amyloid assemblies at synapses, mediated by its intrinsically disordered region (IDR) and leading to permanent physical alterations at the basis of memory persistence. Although the molecular mechanisms by which amyloid formation takes place in CPEB have been described in invertebrates, the way amyloid formation occurs in the human homolog CPEB3 (hCPEB3) remains unclear. Here, we characterize by NMR spectroscopy the atomic level conformation and ps-ms dynamics of the 426-residue IDR of hCPEB3, which has been associated with episodic memory in humans. Results We show that the 426-residue N-terminal region of hCPEB3 is a dynamic, intrinsically disordered region (IDR) which lacks stable folded structures. The first 29 residues, M1QDDLLMDKSKTQPQPQQQQRQQQQPQP29, adopt a helical + disordered motif, and residues 86–93: P83QQPPPP93, and 166–175: P166PPPAPAPQP175 form polyproline II (PPII) helices. The (VG)5 repeat motif is completely disordered, and residues 200–250 adopt three partially populated α-helices. Residues 345–355, which comprise the nuclear localization signal (NLS), form a modestly populated α-helix which may mediate STAT5B binding. These findings allow us to suggest a model for nascent hCPEB3 structural transitions at single residue resolution, advancing that amyloid breaker residues, like proline, are a key difference between functional versus pathological amyloids. Conclusion Our NMR spectroscopic analysis of hCPEB3 provides insights into the first structural transitions involved in protein–protein and protein-mRNA interactions. The atomic level understanding of these structural transitions involved in hCPEB3 aggregation is a key first step toward understanding memory persistence in humans, as well as sequence features that differentiate beneficial amyloids from pathological ones. Areas Biophysics, Structural Biology, Biochemistry & Neurosciences.

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Phase separation modulates the functional amyloid assembly of human CPEB3

Ramírez de Mingo,

López-García,

Vaquero

et al. 2023

Progress in Neurobiology

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Mapping the Fibril Core of the Prion Subdomain of the Mammalian CPEB3 that is Involved in Long Term Memory Retention

Cited by 5 publications

References 60 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

Conformational dynamics in the disordered region of human CPEB3 linked to memory consolidation

Phase separation modulates the functional amyloid assembly of human CPEB3

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