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J Struct Biol. 2019 Jun 3. pii: S1047-8477(19)30130-3. doi: 10.1016/j.jsb.2019.06.001. [Epub ahead of print]

Delving into the amyloidogenic core of human leukocyte chemotactic factor 2.

Author information

1
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: etsiolaki@biol.uoa.gr.
2
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: gnasi@biol.uoa.gr.
3
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: fbaltoumas@biol.uoa.gr.
4
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA. Electronic address: sgutierrez@alnylam.com.
5
Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142, USA. Electronic address: htu@alnylam.com.
6
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 157 01, Greece. Electronic address: veconom@biol.uoa.gr.

Abstract

ALECT2 (leukocyte chemotactic factor 2) amyloidosis is one of the most recently identified amyloid-related diseases, with LECT2 amyloids commonly found in different types of tissues. Under physiological conditions, LECT2 is a 16 kDa multifunctional protein produced by the hepatocytes and secreted into circulation. The pathological mechanisms causing LECT2 transition into the amyloid state are still largely unknown. In the case of ALECT2 patients, there is no disease-causing mutation, yet almost all patients carry a common polymorphism that appears to be necessary but not sufficient to directly trigger amyloidogenesis. In this work, we followed a reductionist methodology in order to detect critical amyloidogenic "hot-spots" during the fibrillation of LECT2. By associating experimental and computational assays, this approach reveals the explicit amyloidogenic core of human LECT2 and pinpoints regions with distinct amyloidogenic properties. The fibrillar architecture of LECT2 polymers, based on our results, provides a wealth of detailed information about the amyloidogenic "hot-spot" interactions and represents a starting point for future peptide-driven intervention in ALECT2 amyloidosis.

KEYWORDS:

AMYLPRED; Aggregation-prone peptides; Amyloids; LECT2 amyloidosis; Prediction

PMID:
31170474
DOI:
10.1016/j.jsb.2019.06.001

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