Selective molecular recognition in amyloid growth and transmission and cross-species barriers

Abstract

Mutual conformational selection and population shift followed by minor induced-fit optimization is the key mechanism in biomolecular recognition, and monomers and small oligomers binding to amyloid seeds in fibril growth is a molecular recognition event. Here, we describe amyloid aggregation, preferred species, cross-species barriers and transmission within the broad framework of molecular recognition. Cross-seeding of amyloid species is governed by conformational selection of compatible (complementary) states. If the dominant conformations of two species are similar, they can cross-seed each other; on the other hand, if they are sufficiently different, they will grow into different fibrils, reflecting species barriers. Such a scenario has recently been observed for the tau protein, which has four repeats. While a construct consisting of repeats 1, 3 and 4 can serve as a seed for the entire four-repeat tau segment, the inverse does not hold. On the other hand, the tau protein repeats with the characteristic U-turn shape can cross-seed Alzheimer's amyloid β and, similarly, the islet amyloid polypeptide. Within this framework, we suggest that the so-called "central dogma" of amyloid formation, where aggregation takes place through nonspecific backbone hydrogen bonding interactions, which are common to all peptides and proteins, is a simple reflection of the heterogeneous, polymorphic free-energy landscape of amyloid species. Here, we review available data and make some propositions addressing this key problem. In particular, we argue that recent theoretical and experimental observations support the key role of selective molecular recognition in amyloidosis and in determining cross-species barriers and transmission.

Figure 1.

An illustration of conformational selection and population shift in protein recognition. Top: four protein conformations with different populations are shown as A, B, C, and D. The ligand may have conformation α, β, γ and δ. The mutual conformational selection between protein and ligands may generate five (roughly typical of real scenario’s) leading conformers: Aα, Bβ, Cγ, Dγ, and Dδ. The Bβ conformer has the highest population in final complex.

Figure 2.

Conformational selection mechanism may operate in the early and late stages of amyloid polymerization. The top yellow box highlights that the initial perturbation or unfolding of the native protein structure can lead to the formation of small oligomers (top yellow box); the formation of nucleation site for further polymerization may take long time for total disordered monomers, with many rounds of association-disassociation events. Partially unfolded proteins, as in the case of domain swapping, may accelerate the formation through direct molecular recognition. The middle panels relate to the formation of larger oligomers. The blue box is the nucleation polymerization pathway and the green box depicts molecular recognition. The middle panel also highlights the formation of spherical particles. In the bottom panel, molecular recognition dominates fibril growth, with possibly leading to polymorphic amyloid states. Molecular recognition takes place via mutual conformation selection and population shift.

Figure 3.

Unlike amyloid seed oligomer, globulomers cannot recruit additional monomers to extend their size through conformation selection. (I) Aβ42 globulomer model with parallel β-sheets (GO1 model). (II) Aβ42 globulomer model with antiparalle β-sheets (GO3 model). The interlocking of two hexamer β-sheets makes the globulomer unable to bind incoming β-strands. (III) The orthogonal β−sheets conformation of the globulomer models is similar to the motif of ‘classical’ fatty acids binding proteins (pdb code: 1eal). (IV). Structure of a traditional amyloid motif with double β−sheets conformation. (V) Structure of a traditional amyloid motif with a triple β−sheets conformation, which may explain E22Q Dutch mutation in Alzeheimer’s Disease.

Figure 4.

Amyloid cross-seed growth is decided by the overlap in the populations of polymorphic amyloid structures. (I) This is the case where both species A and B share a similar structure with high population. The amyloid formation should be transmittable freely between species A and B. (II) If species C has some polymorphic population of an amyloid form which is similar to the seeds from species D, then seeds from species D can recruit and catalyze the amyloid formation of species C. (III) However, because the major amyloid form of species C does not have corresponding polymorphic population in species D, the seeds from species C recruit species D to form amyloid.