Identification of proteins that specifically recognize and bind protofibrillar aggregates of amyloid-β

Wahlberg, ElisabetSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för Molekylära vetenskaper,Department of Molecular Sciences,Affibody AB (författare)

QC 20170818
Protofibrils of the 42 amino acids long amyloid-β peptide are transient pre-fibrillar intermediates in the process of peptide aggregation into amyloid plaques and are thought to play a critical role in the pathology of Alzheimer's disease. Hence, there is a need for research reagents and potential diagnostic reagents for detection and imaging of such aggregates. Here we describe an in vitro selection of Affibody molecules that bind to protofibrils of Aβ42cc, which is a stable engineered mimic of wild type Aβ42 protofibrils. Several binders were identified that bind Aβ42cc protofibrils with low nanomolar affinities, and which also recognize wild type Aβ42 protofibrils. Dimeric head-to-tail fusion proteins with subnanomolar binding affinities, and very slow dissociation off-rates, were also constructed. A mapping of the chemical properties of the side chains onto the Affibody scaffold surface reveals three distinct adjacent surface areas of positively charged surface, nonpolar surface and a polar surface, which presumably match a corresponding surface epitope on the protofibrils. The results demonstrate that the engineered Aβ42cc is a suitable antigen for directed evolution of affinity reagents with specificity for wild type Aβ42 protofibrils.

Rahman, MahafuzurSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för Molekylära vetenskaper,Department of Molecular Sciences(Swepub:slu)96558 (författare)
Lindberg, HannaKTH,Proteinteknologi(Swepub:kth)u1mwn94r (författare)
Gunneriusson, E. (författare)
Schmuck, BenjaminSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för Molekylära vetenskaper,Department of Molecular Sciences(Swepub:slu)97577 (författare)
Lendel, ChristoferSwedish University of Agricultural Sciences,KTH,Tillämpad fysikalisk kemi,Sveriges lantbruksuniversitet, Sverige,Institutionen för Molekylära vetenskaper,Department of Molecular Sciences(Swepub:slu)50320 (författare)
Sandgren, MatsSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för Molekylära vetenskaper,Department of Molecular Sciences(Swepub:slu)49440 (författare)
Löfblom, JohnKTH,Proteinteknologi(Swepub:kth)u1z7cgkl (författare)
Ståhl, StefanKTH,Proteinteknologi(Swepub:kth)u1svy8i4 (författare)
Härd, TorleifSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för Molekylära vetenskaper,Department of Molecular Sciences(Swepub:slu)50056 (författare)
Sveriges lantbruksuniversitetInstitutionen för Molekylära vetenskaper (creator_code:org_t)
Sveriges lantbruksuniversitet

Av författaren/redakt...: Wahlberg, Elisab ...; Rahman, Mahafuzu ...; Lindberg, Hanna; Gunneriusson, E.; Schmuck, Benjami ...; Lendel, Christof ...; visa fler...; Sandgren, Mats; Löfblom, John; Ståhl, Stefan; Härd, Torleif; visa färre...

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