Faculty

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Ansgar B Siemer, PhD
Assistant Professor of Physiology and Neuroscience
Zilkha Neurogenetic Institute
ZNI 113, 1501 San Pablo Street Health Sciences Campus Los Angeles
+1 323 442 2720

Overview

The aim of my laboratory is to create a better understanding of the pathological and functional aspects of protein disorder and aggregation. In particular, we are interested in the differences between functional and pathological amyloid fibrils and the importance of intrinsically disordered protein domains (i.e. domains that lack stable tertiary or secondary structure) for the formation of amyloid.

Amyloid formation is important for many neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease. The aggregation of monomeric proteins into a variety of oligomeric and fibrillar (amyloid) states can lead to cell death and, therefore, disease. However, amyloid fibrils can also have non-pathological, positive functions such as cell signaling or scaffolding functions. One of the most important goals of the lab is to understand what distinguishes functional and pathological amyloid fibrils. Understanding the difference between these types of amyloid could lead to the development of new therapeutics and will deepen our understanding of the role of amyloid in biology.

A second area of research in my laboratory is protein disorder as prerequisite for amyloid formation. Intrinsic disorder or partial unfolding is necessary for a protein to aggregate from its soluble state into an amyloid fibril. Furthermore, many proteins can be forced to fold into an amyloid by partial denaturation in vitro. The structural aspects of the unfolded state is, therefore, important for the understanding of amyloid formation and may lead to new strategies to prevent the formation of amyloid in neurodegenerative diseases. However, partially unfolded, intrinsically disordered proteins also carry important functional aspects, especially in eukaryotic organisms, where up to 40% of all proteins contain disordered regions. Our second goal is to understand how aggregation is prevented in most disordered proteins and why it occurs in some disease-related cases.

To address these questions, my lab will use primarily solid-state nuclear magnetic resonance (NMR) in conjunction with other biochemical methods. Solid-state NMR is an emerging technique that enables us to investigate protein structures that are otherwise inaccessible to atomic-resolution structural methods such as X-ray crystallography and liquid-state NMR, thereby permitting us to investigate systems such as protein fibrils with atomic resolution.

Publications

Metal Binding Properties of the N-Terminus of the Functional Amyloid Orb2. Biomolecules. 2017 Aug 01; 7(3). View in: PubMed

Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils. Biochemistry. 2017 Jul 18; 56(28):3579-3586. View in: PubMed

The Functional Amyloid Orb2A Binds to Lipid Membranes. Biophys J. 2017 Jul 11; 113(1):37-47. View in: PubMed

Identification and Structural Characterization of the N-terminal Amyloid Core of Orb2 isoform A. Sci Rep. 2016 Dec 06; 6:38265. View in: PubMed

Dynamic domains of amyloid fibrils can be site-specifically assigned with proton detected 3D NMR spectroscopy. J Biomol NMR. 2016 Nov; 66(3):159-162. View in: PubMed

Dynamic domains of amyloid fibrils can be site-specifically assigned with proton detected 3D NMR spectroscopy. J Biomol NMR. 2016 Oct 20. View in: PubMed

Solid-State Nuclear Magnetic Resonance on the Static and Dynamic Domains of Huntingtin Exon-1 Fibrils. Biochemistry. 2015 Jun 30; 54(25):3942-9. View in: PubMed

Characterization of prion-like conformational changes of the neuronal isoform of Aplysia CPEB. Nat Struct Mol Biol. 2013 Apr; 20(4):495-501. View in: PubMed

The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012 Jul 20; 150(2):339-50. View in: PubMed

Protein linewidth and solvent dynamics in frozen solution NMR. PLoS One. 2012; 7(10):e47242. View in: PubMed

Homonuclear mixing sequences for perdeuterated proteins. J Magn Reson. 2011 Jan; 208(1):122-7. View in: PubMed

Protein-ice interaction of an antifreeze protein observed with solid-state NMR. Proc Natl Acad Sci U S A. 2010 Oct 12; 107(41):17580-5. View in: PubMed

Solid-state NMR on a type III antifreeze protein in the presence of ice. J Am Chem Soc. 2008 Dec 24; 130(51):17394-9. View in: PubMed

Amyloid fibrils of the HET-s(218-289) prion form a beta solenoid with a triangular hydrophobic core. Science. 2008 Mar 14; 319(5869):1523-6. View in: PubMed

Improved resolution in (13)C solid-state spectra through spin-state-selection. J Magn Reson. 2007 Feb; 184(2):322-9. View in: PubMed

Observation of highly flexible residues in amyloid fibrils of the HET-s prion. J Am Chem Soc. 2006 Oct 11; 128(40):13224-8. View in: PubMed

13C, 15N resonance assignment of parts of the HET-s prion protein in its amyloid form. J Biomol NMR. 2006 Feb; 34(2):75-87. View in: PubMed

Correlation of structural elements and infectivity of the HET-s prion. Nature. 2005 Jun 9; 435(7043):844-8. View in: PubMed

Correlation of structural elements and infectivity of the HET-s prion. Nature. 2005 Jun 09; 435(7043):844-8. View in: PubMed

High-resolution solid-state NMR spectroscopy of the prion protein HET-s in its amyloid conformation. Angew Chem Int Ed Engl. 2005 Apr 15; 44(16):2441-4. View in: PubMed

Conserved asparagine residue 54 of alpha-sarcin plays a role in protein stability and enzyme activity. Biol Chem. 2004 Dec; 385(12):1165-70. View in: PubMed

Fluoroalcohol-induced structural changes of proteins: some aspects of cosolvent-protein interactions. Eur Biophys J. 2001 Aug; 30(4):273-83. View in: PubMed

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