Identification of a Steric Zipper Motif in the Amyloidogenic Core of Human Cystatin C and Its Use for the Design of Self-Assembling Peptides

Abstract

Amyloid fibrils have been known for many years. Unfortunately, their fame stems from negative aspects related to amyloid diseases. Nevertheless, due to their properties, they can be used as interesting nanomaterials. Apart from their remarkable stability, amyloid fibrils may be regarded as a kind of a storage medium and as a source of active peptides. In many cases, their structure may guarantee a controlled and slow release of peptides in their active form; therefore, they can be used as a potential nanomaterial in drug delivery systems. In addition, amyloid fibrils display controllable stiffness, flexibility, and satisfactory mechanical strength. In addition, they can be modified and functionalized very easily. Understanding the structure and genesis of amyloid assemblies derived from a broad range of amyloidogenic proteins could help to better understand and use this unique material. One of the factors responsible for amyloid aggregation is the steric zipper. Here, we report the discovery of steric zipper-forming peptides in the sequence of the amyloidogenic protein, human cystatin C (HCC). The ability of short peptides derived from this fragment of HCC to form fibrillar structures with defined self-association characteristics and the factors influencing this aggregation are also presented in this paper.

Prediction of Aggregation of Biologically-Active Peptides with the UNRES Coarse-Grained Model

“…As shown in Table 1 , the data of 13 of the peptides studies were taken from our previous work [ 27 , 31 , 32 , 34 ]. Three peptides (Tau R2/wt, Tau R3/-P312 and Sup35(7-13) were studied by other researchers [ 28 , 29 , 33 ]; however, we synthesized them and performed measurements in this work.…”

“…In this study, we used the physics-based UNRES coarse-grained model [ 23 , 24 , 25 , 26 ] developed in our laboratory to investigate the association of 16 peptides, whose aggregation has already been studied experimentally [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], as well as of four new peptides. These peptides have sizes ranging from 6 to 32 amino-acid residues and varying contents of hydrophobic, polar and charged residues.…”

“…These peptides have sizes ranging from 6 to 32 amino-acid residues and varying contents of hydrophobic, polar and charged residues. Of those, 12 are hexa- or heptapeptides excised from the -sheet and loop regions of human cystatin C [ 27 , 34 ], the Tau protein [ 28 , 33 ], or the Sup36 prion protein [ 29 , 30 ] and are potentially aggregation-prone.…”