The β-strand D of transthyretin trapped in two discrete conformations

Hörnberg, AndreasUmeå universitet,Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet),Sauer-Eriksson (författare)

Conformational changes in native and variant forms of the human plasma protein transthyretin (TTR) induce several types of amyloid diseases. Biochemical and structural studies have mapped the initiation site of amyloid formation onto residues at the outer C and D beta-strands and their connecting loop. In this study, we characterise an engineered variant of transthyretin, Ala108Tyr/Leu110Glu, which is kinetically and thermodynamically more stable than wild-type transthyretin, and as a consequence less amyloidogenic. Crystal structures of the mutant were determined in two space groups, P2(1)2(1)2 and C2, from crystals grown in the same crystallisation set-up. The structures are identical with the exception for residues Leu55-Leu58, situated at beta-strand D and the following DE loop. In particular, residues Leu55-His56 display large shifts in the C2 structure. There the direct hydrogen bonding between beta-strands D and A has been disrupted and is absent, whereas the beta-strand D is present in the P2(1)2(1)2 structure. This difference shows that from a mixture of metastable TTR molecules, only the molecules with an intact beta-strand D are selected for crystal growth in space group P2(1)2(1)2. The packing of TTR molecules in the C2 crystal form and in the previously determined amyloid TTR (ATTR) Leu55Pro crystal structure is close-to-identical. This packing arrangement is therefore not unique in amyloidogenic mutants of TTR.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
NATURVETENSKAP Biologi Biofysik hsv//swe
NATURAL SCIENCES Biological Sciences Biophysics hsv//eng
Crystallography
X-Ray
Dimerization
Humans
Hydrogen Bonding
Hydrogen-Ion Concentration
Models
Molecular
Mutation
Prealbumin
Protein Conformation
Protein Denaturation

Olofsson, AndersUmeå universitet,Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten),Sauer-Eriksson(Swepub:umu)anol0042 (författare)
Eneqvist, ThereseUmeå universitet,Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet),Sauer-Eriksson (författare)
Lundgren, ErikUmeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Lundgren(Swepub:umu)erlu0003 (författare)
Sauer-Eriksson, ElisabethUmeå universitet,Umeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet),Sauer-Eriksson(Swepub:umu)elsa0002 (författare)
Umeå universitetUmeå centrum för molekylär patogenes (UCMP) (Teknisk-naturvetenskaplig fakultet) (creator_code:org_t)

Ingår i:Biochimica et Biophysica ActaAmsterdam : Elsevier1700:1, s. 93-1040006-30021878-2434
Ingår i:Biochimica et Biophysica Acta (BBA) - Proteins and ProteomicsAmsterdam : Elsevier1700:1, s. 93-1041570-9639

Av författaren/redakt...: Hörnberg, Andrea ...; Olofsson, Anders; Eneqvist, Theres ...; Lundgren, Erik; Sauer-Eriksson, ...

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