Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes

Abstract

The aberrant self-assembly of intrinsically disordered proteins (IDPs) into soluble oligomers and their interactions with biological membranes underlie the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease. Catechins have emerged as useful tools to reduce the toxicity of IDP oligomers by modulating their interactions with membranes. However, the structural determinants of catechin binding to IDP oligomers and membranes remain largely elusive. Here, we assemble a catechin library by combining several naturally occurring chemical modifications and, using a coupled NMR-statistical approach, we map at atomic resolution the interactions of such library with the Alzheimer’s-associated amyloid-beta (Aβ) oligomers and model membranes. Our results reveal multiple catechin affinity drivers and show that the combination of affinity-reducing covalent changes may lead to unexpected net gains in affinity. Interestingly, we find that the positive cooperativity is more prevalent for Aβ oligomers than membrane binding, and that the determinants underlying catechin recognition by membranes are markedly different from those dissected for Aβ oligomers. Notably, we find that the unanticipated positive cooperativity arises from the critical regulatory role of the gallate catechin moiety, which recruits previously disengaged substituents into the binding interface and leads to an overall greater compaction of the receptor-bound conformation. Overall, the previously elusive structural attributes mapped here provide an unprecedented foundation to establish structure-activity relationships of catechins. The aberrant self-assembly of intrinsically disordered proteins (IDPs) into soluble oligomers and their interactions with biological membranes underlie the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease. Catechins have emerged as useful tools to reduce the toxicity of IDP oligomers by modulating their interactions with membranes. However, the structural determinants of catechin binding to IDP oligomers and membranes remain largely elusive. Here, we assemble a catechin library by combining several naturally occurring chemical modifications and, using a coupled NMR-statistical approach, we map at atomic resolution the interactions of such library with the Alzheimer’s-associated amyloid-beta (Aβ) oligomers and model membranes. Our results reveal multiple catechin affinity drivers and show that the combination of affinity-reducing covalent changes may lead to unexpected net gains in affinity. Interestingly, we find that the positive cooperativity is more prevalent for Aβ oligomers than membrane binding, and that the determinants underlying catechin recognition by membranes are markedly different from those dissected for Aβ oligomers. Notably, we find that the unanticipated positive cooperativity arises from the critical regulatory role of the gallate catechin moiety, which recruits previously disengaged substituents into the binding interface and leads to an overall greater compaction of the receptor-bound conformation. Overall, the previously elusive structural attributes mapped here provide an unprecedented foundation to establish structure-activity relationships of catechins. The self-association of intrinsically disordered proteins (IDPs) into toxic oligomers underlies the pathogenesis of several neurodegenerative and non-neuropathic systemic disorders (1Chiti F. Dobson C.M. Protein misfolding, functional amyloid, and human disease.Annu. Rev. Biochem. 2006; 75: 333-366Google Scholar, 2Chiti F. Dobson C.M. Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade.Annu. Rev. Biochem. 2017; 86: 27-68Google Scholar). One of the key mechanisms by which oligomers confer toxicity is through disrupting the integrity of biological membranes (3Lee S.J.C. Nam E. Lee H.J. Savelieff M.G. Lim M.H. Towards an understanding of amyloid-β oligomers: Characterization, toxicity mechanisms, and inhibitors.Chem. Soc. Rev. 2017; 46: 310-323Google Scholar). Thus, it is critical to identify compounds that modulate the deleterious interactions of IDP oligomers with membranes. In this regard, several classes of compounds have been identified to date, including small molecules (4Ahmed R. Akcan M. Khondker A. Rheinstädter M.C. Bozelli J.C. Epand R.M. Huynh V. Wylie R.G. Boulton S. Huang J. Verschoor C.P. Melacini G. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.Chem. Sci. 2019; 10: 6072-6082Google Scholar, 5Ahmed R. Melacini G. A solution NMR toolset to probe the molecular mechanisms of amyloid inhibitors.Chem. Commun. 2018; 54: 4644-4652Google Scholar, 6Ahmed R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar, 7Fusco G. Chen S.W. Williamson P.T.F. Cascella R. Perni M. Jarvis J.A. Cecchi C. Vendruscolo M. Chiti F. Cremades N. Ying L. Dobson C.M. de Simone A. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers.Science. 2017; 358: 1440-1443Google Scholar, 8García-Viñuales S. Ahmed R. Sciacca M.F.M. Lanza V. Giuffrida M.L. Zimbone S. Romanucci V. Zarrelli A. Bongiorno C. Spinella N. Galati C. Di Fabio G. Melacini G. Milardi D. Trehalose conjugates of silybin as prodrugs for targeting toxic Aβ aggregates.ACS Chem. Neurosci. 2020; 11: 2566-2576Google Scholar, 9Sironi E. Colombo L. Lompo A. Messa M. Bonanomi M. Regonesi M.E. Salmona M. Airoldi C. 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Rheinstädter M.C. Bozelli J.C. Epand R.M. Huynh V. Wylie R.G. Boulton S. Huang J. Verschoor C.P. Melacini G. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.Chem. Sci. 2019; 10: 6072-6082Google Scholar, 6Ahmed R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar, 7Fusco G. Chen S.W. Williamson P.T.F. Cascella R. Perni M. Jarvis J.A. Cecchi C. Vendruscolo M. Chiti F. Cremades N. Ying L. Dobson C.M. de Simone A. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers.Science. 2017; 358: 1440-1443Google Scholar, F. A. M.C. into the of and the aggregation of by of molecular J. Sci. 2020; Scholar, J. A. M. L. R. S. A. into Scholar, J. J. α-synuclein and amyloid-β and cellular toxicity.Proc. Natl. Acad. Sci. U. S. A. Scholar). and catechins species of amyloid-beta (Aβ) and several such as and J. A. M. L. R. S. A. into Scholar, G. M. Vendruscolo M. Dobson C.M. de Simone A. Molecular determinants of the interaction of with and disordered 2018; Scholar, J. A. X. L. L. M. C. X. et intrinsically disordered of and Commun. Scholar, H.J. A. M.I. J. The green tea polyphenol (−)-epigallocatechin gallate the aggregation of into toxic oligomers at Scholar, P. the in amyloid and the of of Am. Chem. Soc. 2014; Scholar, by of by Scholar). Molecular have that the of Aβ with to the of F. A. M.C. into the of and the aggregation of by of molecular J. Sci. 2020; Scholar). In we previously by NMR that Aβ oligomers at multiple and with a affinity R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar). In Aβ more with R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar, G. M. Vendruscolo M. Dobson C.M. de Simone A. Molecular determinants of the interaction of with and disordered 2018; Scholar, of the molecular interactions amyloid and Chem. B. 114: Scholar). Wang et of the molecular interactions amyloid and Chem. B. 114: that the binding of to Aβ a of with largely In et G. M. Vendruscolo M. Dobson C.M. de Simone A. Molecular determinants of the interaction of with and disordered 2018; through NMR that the of in with the binding the catechin and Aβ results that the binding of catechins to Aβ species largely for their amyloid progress in understanding the interactions catechins and the IDP oligomers the underlying mechanism of largely elusive. is catechins as chemical of and the of as to the catechins (4Ahmed R. Akcan M. Khondker A. Rheinstädter M.C. Bozelli J.C. Epand R.M. Huynh V. Wylie R.G. Boulton S. Huang J. Verschoor C.P. Melacini G. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.Chem. Sci. 2019; 10: 6072-6082Google Scholar, 6Ahmed R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar, 7Fusco G. Chen S.W. Williamson P.T.F. Cascella R. Perni M. Jarvis J.A. Cecchi C. Vendruscolo M. Chiti F. Cremades N. Ying L. Dobson C.M. de Simone A. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers.Science. 2017; 358: 1440-1443Google Scholar, F. A. M.C. into the of and the aggregation of by of molecular J. Sci. 2020; Scholar, U. M. G. J. Reif B. Structural of nontoxic Aβ oligomers.J. Scholar, Lee J. the molecular by which amyloid Am. Chem. Soc. Scholar). it to the in arises from the binding of catechins to IDP oligomers membranes. the understanding of catechin to IDP membrane binding is at this and the drivers of interactions is to the of amyloid inhibitors with and E. Colombo L. Lompo A. Messa M. Bonanomi M. Regonesi M.E. Salmona M. Airoldi C. Natural compounds against neurodegenerative diseases: Molecular characterization of the interaction of catechins from green tea with Aβ1–42, PrP106–126, and ataxin-3 oligomers.Chem. Eur. J. 2014; 20: 13793-13800Google Scholar, Lee J. the molecular by which amyloid Am. Chem. Soc. Scholar, Ahmed R. Melacini G. Catechins as tools to the molecular basis of 2020; Scholar, S. P. E. G. D. C. L. C. L. J. C. G. C. et and in identify a Aβ in and Aβ and in an model of Alzheimer’s Chem. Neurosci. 2019; 10: Scholar). In an to establish structure-activity relationships for we a of a IDP to toxic that amyloid beta to biological membrane that small and a catechin The catechin library from the and combining three modifications that the catechin A to the of the in by the in the of by the in and the of the by the in The library and the gallate of the library we for oligomers and the binding and the interactions to oligomers membranes. The through and to the key drivers of catechin interactions with Aβ oligomers and membranes. The of the for catechin library the of catechin to the binding affinity for Aβ oligomers membranes. In the of binding and interactions a structural the interactions of with the this approach, we membrane in of catechin interactions and underlying including the to which covalent modifications to the overall we show that catechin library with Aβ oligomers and of interactions with Aβ toxicity Thus, the structural from this a foundation to catechin the of catechin to binding, we for the catechins in library through of such reveals that library by of in the to The to the binding affinity of from the of and the gallate In from to the by and the of results in a of affinity for oligomers and in catechin library are to from in the as by the in for different catechin R. Huang J. M. T. Melacini G. Atomic resolution map of self-assembly for an through Am. Chem. Soc. Scholar, V. R. Melacini G. through Am. Chem. Soc. Scholar, J. V. R. Melacini G. the molecular basis for the of the by human using and NMR Am. Chem. Soc. Scholar, Ying J. R. the of amyloid-β by solution of oligomers. the affinity the catechin library is to in to binding and in in the gallate However, it is that such are of the gallate of to and the binding the of as in the binding affinity the the and gallate to binding, we a that the catechin the and and the as in The binding is by the with positive the of is that the and gallate catechin to binding positive the the and to binding through a that the and and the as in In this the binding by the is the of is which is and to the of positive cooperativity the and to reveal that catechin binding to oligomers is by the of the in with the of and the gallate the gallate is to oligomers with as by the for to binding are in the interactions catechins and we affinity to the for the catechin library to probe the interactions this and to for an membrane Aβ oligomers binding we the for the Aβ oligomers. The and are in The catechins membranes with in the the for oligomers and membranes and the for Aβ oligomers is to a in the of membrane binding, for which a more of is The drivers of binding, that the and the gallate to to membrane binding A and the of the affinity for membranes than it Overall, reveal markedly different in the for catechin binding to oligomers membranes Interestingly, the cooperativity the and from positive to in the of membrane binding In the the and gallate substituents is in from oligomers to membranes and the gallate the catechin to the of the library show oligomers and membranes in of the determinants and their cooperativity into such membrane and to the modifications to binding, we mapped the and the changes in catechin of catechins and to oligomers and membranes. and for and and are in are in that with the the of and in the and membrane with and of and as and as and we mapped for of the catechins in library the for binding oligomers and and membranes and the catechin for the for catechins are those of in A A and and to A A and and A and as the to and are to a of to A and the for is that the of the are catechin library and are the of the A and in the of we from oligomers to and In catechins and into the binding as by the a for the cooperativity the and gallate modifications the of of the for it the and the catechins in library their binding we that catechins are from those reveal that the in Aβ binding as A with as a critical that as a of and C. to are to the interactions with we to interactions and to the of Aβ binding, for membrane binding, A the with the for catechins and and However, in the of the catechin library for the of to the is with the more of binding catechin library in the of membranes of in of from membranes to and to a of the and for Aβ oligomers are with the in positive cooperativity the binding of the in and the gallate In catechins from catechins the binding Overall, the of binding catechin library reveal that the and for Aβ binding are in the of membrane binding Aβ membrane in catechin we to probe the interactions through and probe the interactions the different catechin in the and we for of catechin and and in the of Aβ oligomers and membranes and The and are in the of and of In we more in the of than in the of the catechins a more catechin binding to Aβ oligomers membranes. However, the of compaction binding for Aβ oligomers membranes. that the in the of the catechin library are more in the of Aβ oligomers than membranes. to the of more interactions catechin for oligomers The catechin compaction for Aβ oligomers membranes with the positive cooperativity to binding for oligomers membranes The more of catechins to oligomers membranes is with the by the binding for Aβ for membranes and Our catechin library the combination of the and gallate modifications of and key attributes of catechin recognition by Aβ oligomers and which are in and C. The to catechins to Aβ oligomers are A and is a as A and as Aβ for gallate catechins in In the A and have been for catechin binding to of different including Aβ to and from the and ataxin-3 proteins E. Colombo L. Lompo A. Messa M. Bonanomi M. Regonesi M.E. Salmona M. Airoldi C. Natural compounds against neurodegenerative diseases: Molecular characterization of the interaction of catechins from green tea with Aβ1–42, PrP106–126, and ataxin-3 oligomers.Chem. Eur. J. 2014; 20: 13793-13800Google Scholar). as of the for Aβ oligomers recruits and which as Aβ binding, and a with this the of the and to Aβ are more than that of In the binding of positive cooperativity with those of the in a of the catechin library the The of the gallate to Aβ affinity is as by binding of catechins with and the gallate to of E. Colombo L. Lompo A. Messa M. Bonanomi M. Regonesi M.E. Salmona M. Airoldi C. Natural compounds against neurodegenerative diseases: Molecular characterization of the interaction of catechins from green tea with Aβ1–42, PrP106–126, and ataxin-3 oligomers.Chem. Eur. J. 2014; 20: 13793-13800Google as as C. Chen G. tea and mechanisms in disrupting Chem. Neurosci. 2020; 11: Scholar, J. P. V. of the and compounds small oligomers of amyloid Aβ Chem. 2020; Scholar). The have of the gallate from the interaction with Aβ to with the of interactions in of more in the of C. Chen G. tea and mechanisms in disrupting Chem. Neurosci. 2020; 11: Scholar). the of and may the previously for binding to oligomers R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar). different recognition are for binding of catechin library to membranes a identified and the by and membrane binding is than in the of Aβ binding leads to in the positive cooperativity and and to an overall more of binding the catechin library In in the of and are affinity and the of to binding are different from the more of to Aβ binding is to that the catechin here the of to which is to probe results in which interactions with more to binding, such as and which catechin for membranes in the T. S. F. T. of tea catechins with with Biochem. Scholar, S. T. of the interaction of tea catechins with Biochem. Scholar). Notably, different from for that may catechin and and different T. S. F. T. of tea catechins with with Biochem. Scholar, S. T. of the interaction of tea catechins with Biochem. Scholar). such may at for of the different by it is that catechins membranes at multiple with a of and the the Interestingly, in the of the key affinity determinants to more to those identified here for Aβ oligomers. the in and the gallate are drivers of membrane binding, in with the that the key determinants of interactions are the catechin and A.K. M. Molecular the interactions of green tea catechins with of Chem. 56: with and interactions M. T. S. A. T. of gallate with membranes as by NMR Scholar). The of to reduce affinity for the binding of membranes T. S. F. T. of tea catechins with with Biochem. Scholar, S. T. of the interaction of tea catechins with Biochem. the the determinants of Aβ binding and those of membrane Notably, the binding of catechins to membranes to with the cellular of Aβ oligomers as as the catechin for the Aβ oligomers is the in that the catechin binding to the Aβ is more to the of the than the interactions of catechins with membranes. However, membrane binding is to an role in understanding the mechanism of of catechins as inhibitors of may as catechin that with Aβ oligomers for binding to In interactions are for catechins the membranes of and the mechanism of of catechins as of as and J. J. T. E. of a of green J. Scholar, T. T. catechins the Scholar, M. T. of (−)-epigallocatechin gallate the of human Scholar). In the here provide unprecedented the of catechins. we the role of the gallate as a of catechin interactions with is to catechin to the binding Notably, this is as the the catechin is binding to oligomers membranes. results the of the solution NMR and here to the drivers of small molecule binding to as by the of and and from with a greater than A solution in in with Aβ as a from with greater than and as previously (4Ahmed R. Akcan M. Khondker A. Rheinstädter M.C. Bozelli J.C. Epand R.M. Huynh V. Wylie R.G. Boulton S. Huang J. Verschoor C.P. Melacini G. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.Chem. Sci. 2019; 10: 6072-6082Google Scholar). of in of and to a of with The solution and in to a of The solution in into and at The oligomers through a of a previously (4Ahmed R. Akcan M. Khondker A. Rheinstädter M.C. Bozelli J.C. Epand R.M. Huynh V. Wylie R.G. Boulton S. Huang J. Verschoor C.P. Melacini G. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.Chem. Sci. 2019; 10: 6072-6082Google Scholar, 6Ahmed R. VanSchouwen B. Jafari N. Ni X. Ortega J. Melacini G. Molecular mechanism for the (−)-epigallocatechin gallate-induced toxic to nontoxic remodeling of Aβ oligomers.J. Am. Chem. Soc. 2017; 139: 13720-13734Google Scholar). in to a of and at for In of a of as previously (4Ahmed R. Akcan M. Khondker A. Rheinstädter M.C. Bozelli J.C. Epand R.M. Huynh V. Wylie R.G. Boulton S. Huang J. Verschoor C.P. Melacini G. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces.Chem. Sci. 2019; 10: 6072-6082Google Scholar). NMR at a with a and with NMR those previously by et E. Colombo L. Lompo A. Messa M. Bonanomi M. Regonesi M.E. Salmona M. Airoldi C. Natural compounds against neurodegenerative diseases: Molecular characterization of the interaction of catechins from green tea with Aβ1–42, PrP106–126, and ataxin-3 oligomers.Chem. Eur. J. 2014; 20: 13793-13800Google Scholar). are R. Melacini G. A solution NMR toolset to probe the molecular mechanisms of amyloid inhibitors.Chem. Commun. 2018; 54: 4644-4652Google Scholar, B. T. NMR for screening and binding to Chem. Scholar, M. B. of binding by NMR Chem. Scholar, C. M. S. M. R. M. M. High-throughput screening with binding Am. Chem. Soc. with as to and a of of oligomers membranes through and for oligomers and using a of of by a A to that with catechin of through with and a of at The in the and to for in the of for by the at catechin using the of the catechin in the Notably, the for the binding for catechins that the from results in The the in the is the in the and is the of The binding using the to a model the of multiple that are in and is the of catechin and is an over the of oligomers The catechin for binding to the oligomers membranes through the of catechin at the membrane is the of M. B. by NMR to identify of a in with a Am. Chem. Soc. the for to the with the that of which to The NMR at the of that using catechin of and and membrane of and The with a of and and of for A of to the NMR in the for the NMR with catechin of The with a of and and of for The for the including and the changes in binding covalent in catechin the of from catechins and with the The into to their in the catechin to to the the of the to the of the gallate the of to the catechin the of the catechins in library and to those for catechins of gallate and and with to the of the binding changes to the catechin to the binding in the and of the structural The is by the and the is by the the The of the is through the which using a as in of the binding are through the the and of the in the identify structural that the in binding of the catechins in the of oligomers of the the for catechin for the different catechins to a The of catechins in using the for the to the The by through the and the using catechin for the The and in the and using the The and in by to the is in is in and the is in in are of the three of the for catechins in the and by the for a catechin to the in the The for the in a including those and the and the as a and with to the of the the and are the and the from the The that have of with the of this J.C. Bozelli and R. Epand for and the small by the Natural and of R. A. and G. M. R. A. and G. M. R. A. R. R. and G. R. A. and J. R. M. and G. M. R. J. R. M. and G. M. and R. A. and G. M. G. M. G. M. G. M. by the of to R.

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