Chameleon ‘aggregation-prone’ segments of apoA-I: A model of amyloid fibrils formed in apoA-I amyloidosis

Louros, Nikolaos; Tsiolaki, Paraskevi L.; Griffin, Michael D. W.; Howlett, Geoffrey J.; Hamodrakas, Stavros J.; Iconomidou, Vassiliki A.

doi:10.1016/j.ijbiomac.2015.05.032

Cited by 28 publications

(25 citation statements)

References 45 publications

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“…4B, C), which are predicted to form the major amyloid hot spot. 2,22–25 In the crystal structure, these residues form a well-ordered kinked helical segment in the middle of the helix bundle (Fig. 1B, blue), which is consistent with the slow deuteration of this segment observed in the WT (Fig.…”

Section: Resultssupporting

confidence: 79%

“…Although the extended segment 44–55 is largely polar and is predicted not to have high amyloidogenic potential, 2 it was proposed to facilitate α-helix to β-sheet conversion, 17,21 and peptide fragments encompassing this segment can form amyloid fibrils in vitro . 17,23,25 Lack of mutational effects in the HDX of segment 44–55 (Fig. 4E, F) suggests that changes to the native state of this largely unprotected segment 34 do not occur on the time scale of labeling used here, or do not occur at all.…”

Section: Resultsmentioning

confidence: 90%

“…Residue segments that were proposed to be important for amyloidosis are indicated: 14–22 (blue) is the major predicted amyloid “hot spot”; 53–58 (teal) and 69–72 (yellow) are weakly predicted amyloid “hot spots”; 44–55 is the sole β-strand-like segment in the crystal structure; 83–93 contain the cleavage sites generating 1–83 to 1–93 fragments found in AApoAI deposits; and 227–232 (red) is the predicted C-terminal amyloid “hot spot”. 21–25 The latter segment overlaps the α-helix forming the primary lipid binding site.…”

Section: Figurementioning

confidence: 99%

“…22–25 These amyloid “hot spots” are normally protected from misfolding by their native α-helical structure in free (Fig. 1B) or lipid-bound apoA-I.…”

Section: Introductionmentioning

confidence: 99%

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Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?

Das

Wilson

Mei

et al. 2016

Journal of Molecular Biology

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ApoA-I, the major protein of plasma high-density lipoprotein, removes cellular cholesterol and protects against atherosclerosis. ApoA-I mutations can cause familial amyloidosis, a life-threatening disease wherein N-terminal protein fragments form fibrils in vital organs. To unveil the protein misfolding mechanism and to understand why some mutations cause amyloidosis while others do not, we analyzed the structure, stability and lipid-binding properties of naturally occurring mutants of full-length human apoA-I causing either amyloidosis (G26R, W50R, F71Y, L170P) or aberrant lipid metabolism (L159R). Global and local protein conformation and dynamics in solution were assessed by circular dichroism, fluorescence, and hydrogen-deuterium exchange mass spectrometry. All mutants showed increased deuteration in residues 14–22, supporting our hypothesis that decreased protection of this major amyloid “hot spot” can trigger protein misfolding. In addition, L159R showed local helical unfolding near the mutation site, consistent with cleavage of this mutant in plasma to generate the labile 1–159 fragment. Together, the results suggest that reduced protection of the major amyloid “hot spot”, combined with structural integrity of the native helix-bundle conformation, shift the balance from protein clearance to β-aggregation. A delicate balance between the overall structural integrity of a globular protein and the local destabilization of its amyloidogenic segments may be a fundamental determinant of this and other amyloid diseases. Furthermore, mutation-induced conformational changes observed in the helix bundle, which comprises N-terminal 75% of apoA-I, and its flexible C-terminal tail suggest the propagation of structural perturbations to distant sites via an unexpected template-induced ensemble-based mechanism, challenging the classical structure-based view.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 90%

Section: Figurementioning

confidence: 99%

“…22–25 These amyloid “hot spots” are normally protected from misfolding by their native α-helical structure in free (Fig. 1B) or lipid-bound apoA-I.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?

Das

Wilson

Mei

et al. 2016

Journal of Molecular Biology

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“…1C, E,F). Such an apparent morphological polymorphism of amyloid fibrils has been exhibited by many different amyloid-forming proteins or peptides [31,34,49,50].…”

Section: Resultsmentioning

confidence: 99%

A common ‘aggregation‐prone’ interface possibly participates in the self‐assembly of human zona pellucida proteins

et al. 2016

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Human zona pellucida (ZP) is composed of four glycoproteins, namely ZP1, ZP2, ZP3 and ZP4. ZP proteins form heterodimers, which are incorporated into filaments through a common bipartite polymerizing component, designated as the ZP domain. The latter is composed of two individually folded subdomains, named ZP-N and ZP-C. Here, we have synthesized six 'aggregation-prone' peptides, corresponding to a common interface of human ZP2, ZP3 and ZP4. Experimental results utilizing electron microscopy, X-ray diffraction, ATR FT-IR spectroscopy and polarizing microscopy indicate that these peptides self-assemble forming fibrils with distinct amyloid-like features. Finally, by performing detailed modeling and docking, we attempt to shed some light in the self-assembly mechanism of human ZP proteins.

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Identification of an amyloid fibril forming segment of human Pmel17 repeat domain (RPT domain)

Louros

Iconomidou

2016

Biopolymers

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Pmel17 is the major component of functional amyloid fibrils that have an important role during pigment deposition. Pmel17 polymerization is promoted within the mildly acidic conditions of melanosomes, organelles located in pigment-specific cells. A repeat domain (RPT domain) of Pmel17, rich in glutamic acid residues has been extensively associated with the formation of the fibrous matrix. Here, we examine the RPT domain of human Pmel17 in order to provide information on this mechanism. Specifically, we have identified an aggregation-prone peptide segment ((405) VSIVVLSGT(413) ), close to the C-terminal part of the RPT domain. Experimental results utilizing electron microscopy, X-ray fiber diffraction, Congo red staining and ATR FT-IR spectroscopy indicate that this peptide segment self-assembles forming fibrils with evident amyloidogenic properties. Conclusively, our results demonstrate that the (405) VSIVVLSGT(413) peptide segment possibly has an essential role in RPT domain fibrillogenesis.

show abstract

Chameleon ‘aggregation-prone’ segments of apoA-I: A model of amyloid fibrils formed in apoA-I amyloidosis

Cited by 28 publications

References 45 publications

Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?

Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?

A common ‘aggregation‐prone’ interface possibly participates in the self‐assembly of human zona pellucida proteins

Identification of an amyloid fibril forming segment of human Pmel17 repeat domain (RPT domain)

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