Andrew Beel

All Publications

• Structure of mitotic chromosomes. Molecular cell Beel, A. J., Azubel, M., Mattei, P., Kornberg, R. D. 2021

  Abstract

  Chromatin fibers must fold or coil in the process of chromosome condensation. Patterns of coiling have been demonstrated for reconstituted chromatin, but the actual trajectories of fibers in condensed states of chromosomes could not be visualized because of the high density of the material. We have exploited partial decondensation of mitotic chromosomes to reveal their internal structure at sub-nucleosomal resolution by cryo-electron tomography, without the use of stains, fixatives, milling, or sectioning. DNA gyres around nucleosomes were visible, allowing the nucleosomes to be identified and their orientations to be determined. Linker DNA regions were traced, revealing the trajectories of the chromatin fibers. The trajectories were irregular, with almost no evidence of coiling and no short- or long-range order of the chromosomal material. The 146-bp core particle, long known as a product of nuclease digestion, is identified as the native state of the nucleosome, with no regular spacing along the chromatin fibers.

  View details for DOI 10.1016/j.molcel.2021.08.020

  View details for PubMedID 34520722

• 3D genomics across the tree of life reveals condensin II as a determinant of architecture type. Science (New York, N.Y.) Hoencamp, C., Dudchenko, O., Elbatsh, A. M., Brahmachari, S., Raaijmakers, J. A., van Schaik, T., Sedeño Cacciatore, Á., Contessoto, V. G., van Heesbeen, R. G., van den Broek, B., Mhaskar, A. N., Teunissen, H., St Hilaire, B. G., Weisz, D., Omer, A. D., Pham, M., Colaric, Z., Yang, Z., Rao, S. S., Mitra, N., Lui, C., Yao, W., Khan, R., Moroz, L. L., Kohn, A., St Leger, J., Mena, A., Holcroft, K., Gambetta, M. C., Lim, F., Farley, E., Stein, N., Haddad, A., Chauss, D., Mutlu, A. S., Wang, M. C., Young, N. D., Hildebrandt, E., Cheng, H. H., Knight, C. J., Burnham, T. L., Hovel, K. A., Beel, A. J., Mattei, P. J., Kornberg, R. D., Warren, W. C., Cary, G., Gómez-Skarmeta, J. L., Hinman, V., Lindblad-Toh, K., Di Palma, F., Maeshima, K., Multani, A. S., Pathak, S., Nel-Themaat, L., Behringer, R. R., Kaur, P., Medema, R. H., van Steensel, B., de Wit, E., Onuchic, J. N., Di Pierro, M., Lieberman Aiden, E., Rowland, B. D. 2021; 372 (6545): 984-989

  Abstract

  We investigated genome folding across the eukaryotic tree of life. We find two types of three-dimensional (3D) genome architectures at the chromosome scale. Each type appears and disappears repeatedly during eukaryotic evolution. The type of genome architecture that an organism exhibits correlates with the absence of condensin II subunits. Moreover, condensin II depletion converts the architecture of the human genome to a state resembling that seen in organisms such as fungi or mosquitoes. In this state, centromeres cluster together at nucleoli, and heterochromatin domains merge. We propose a physical model in which lengthwise compaction of chromosomes by condensin II during mitosis determines chromosome-scale genome architecture, with effects that are retained during the subsequent interphase. This mechanism likely has been conserved since the last common ancestor of all eukaryotes.

  View details for DOI 10.1126/science.abe2218

  View details for PubMedID 34045355

• Ground-glass opacity heralding invasive lung adenocarcinoma with prodromal dermatomyositis: a case report JOURNAL OF CARDIOTHORACIC SURGERY Beel, A. J., Demos, D. S., Chung, A., Liao, C., Lui, N. S. 2018; 13: 20

  Abstract

  Dermatomyositis, an inflammatory myopathy with cutaneous involvement, is associated with malignancy and often manifests paraneoplastically. While co-occurrence with small cell carcinoma is well attested, primary lung adenocarcinoma, which may present as focal ground-glass opacification on computed tomography of the thorax, is less frequently coincident.We report the case of a 72-year-old female patient with dermatomyositis - treated with a combination of prednisone, methotrexate, and intravenous immunoglobulin - and an indolent, subsolid, non-hypermetabolic pulmonary lesion, which was determined to be invasive primary lung adenocarcinoma. Supporting a paraneoplastic basis, immunosuppressive therapy was discontinued following tumor excision without relapse of signs or symptoms of dermatomyositis.While dermatomyositis prodromal to lung adenocarcinoma is not without precedent, association with an indolent, subsolid lesion has, to the best of our knowledge, not been reported. The case described herein illustrates the importance of maintaining a high index of suspicion for malignancy in the setting of dermatomyositis.

  View details for PubMedID 29415746

• The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol SCIENCE Barrett, P. J., Song, Y., Van Horn, W. D., Hustedt, E. J., Schafer, J. M., Hadziselimovic, A., Beel, A. J., Sanders, C. R. 2012; 336 (6085): 1168-1171

  Abstract

  C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release the amyloid-β polypeptides, which are associated with Alzheimer's disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved α helix, making it well suited for processive cleavage by γ-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer's therapeutics.

  View details for DOI 10.1126/science.1219988

  View details for Web of Science ID 000304647900052

  View details for PubMedID 22654059

  View details for PubMedCentralID PMC3528355

• Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS Beel, A. J., Sakakura, M., Barrett, P. J., Sanders, C. R. 2010; 1801 (8): 975-982

  Abstract

  It is generally believed that cholesterol homoeostasis in the brain is both linked to and impacted by Alzheimer's disease (AD). For example, elevated levels of cholesterol in neuronal plasma and endosome membranes appear to be a pro-amyloidogenic factor. The recent observation that the C-terminal transmembrane domain (C99, also known as the beta-C-terminal fragment, or beta-CTF) of the amyloid precursor protein (APP) specifically binds cholesterol helps to tie together previously loose ends in the web of our understanding of Alzheimer's-cholesterol relationships. In particular, binding of cholesterol to C99 appears to favor the amyloidogenic pathway in cells by promoting localization of C99 in lipid rafts. In turn, the products of this pathway-amyloid-beta and the intracellular domain of the APP (AICD)-may down-regulate ApoE-mediated cholesterol uptake and cholesterol biosynthesis. If confirmed, this negative-feedback loop for membrane cholesterol levels has implications for understanding the function of the APP and for devising anti-amyloidogenic preventive strategies for AD.

  View details for DOI 10.1016/j.bbalip.2010.03.008

  View details for Web of Science ID 000279476000030

  View details for PubMedID 20304095

  View details for PubMedCentralID PMC2886191

• The impact of window functions on NMR-based paramagnetic relaxation enhancement measurements in membrane proteins BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES Van Horn, W. D., Beel, A. J., Kang, C., Sanders, C. R. 2010; 1798 (2): 140-149

  Abstract

  Though challenging, solution NMR spectroscopy allows fundamental interrogation of the structure and dynamics of membrane proteins. One major technical hurdle in studies of helical membrane proteins by NMR is the difficulty of obtaining sufficient long range NOEs to determine tertiary structure. For this reason, long range distance information is sometimes sought through measurement of paramagnetic relaxation enhancements (PRE) of NMR nuclei as a function of distance from an introduced paramagnetic probe. Current PRE interpretation is based on the assumption of Lorentzian resonance lineshapes. However, in order to optimize spectral resolution, modern multidimensional NMR spectra are almost always subjected to resolution-enhancement, leading to distortions in the Lorentizian peak shape. Here it is shown that when PREs are derived using peak intensities (i.e., peak height) and linewidths from both real and simulated spectra that were produced using a wide range of apodization/window functions, that there is little variation in the distances determined (<1 A at the extremes). This indicates that the high degree of resolution enhancement required to obtain well-resolved spectra from helical membrane proteins is compatible with the use of PRE data as a source of distance restraints. While these conclusions are particularly important for helical membrane proteins, they are generally applicable to all PRE measurements made using resolution-enhanced data.

  View details for DOI 10.1016/j.bbamem.2009.08.022

  View details for Web of Science ID 000274859300011

  View details for PubMedID 19751702

  View details for PubMedCentralID PMC2812639

• Nonspecificity of Binding of gamma-Secretase Modulators to the Amyloid Precursor Protein BIOCHEMISTRY Beel, A. J., Barrett, P., Schnier, P. D., Hitchcock, S. A., Bagal, D., Sanders, C. R., Jordan, J. B. 2009; 48 (50): 11837-11839

  Abstract

  Evidence that certain gamma-secretase modulators (GSMs) target the 99-residue C-terminal domain (C99) of the amyloid precursor protein, a substrate of gamma-secretase, but not the protease complex itself has been presented [Kukar, T. L., et al. (2008) Nature 453, 925-929]. Here, NMR results demonstrate a lack of specific binding of these GSMs to monodisperse C99 in LMPG micelles. In addition, results indicate that C99 was likely to have been aggregated in some of the key experiments of the previous work and that binding of GSMs to these C99 aggregates is also of a nonspecific nature.

  View details for DOI 10.1021/bi901839d

  View details for Web of Science ID 000272645400003

  View details for PubMedID 19928774

  View details for PubMedCentralID PMC2794937

• Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): Does APP function as a cholesterol sensor? BIOCHEMISTRY Beel, A. J., Mobley, C. K., Kim, H. J., Tian, F., Hadziselimovic, A., Jap, B., Prestegard, J. H., Sanders, C. R. 2008; 47 (36): 9428-9446

  Abstract

  The amyloid precursor protein (APP) is subject to alternative pathways of proteolytic processing, leading either to production of the amyloid-beta (Abeta) peptides or to non-amyloidogenic fragments. Here, we report the first structural study of C99, the 99-residue transmembrane C-terminal domain of APP liberated by beta-secretase cleavage. We also show that cholesterol, an agent that promotes the amyloidogenic pathway, specifically binds to this protein. C99 was purified into model membranes where it was observed to homodimerize. NMR data show that the transmembrane domain of C99 is an alpha-helix that is flanked on both sides by mostly disordered extramembrane domains, with two exceptions. First, there is a short extracellular surface-associated helix located just after the site of alpha-secretase cleavage that helps to organize the connecting loop to the transmembrane domain, which is known to be essential for Abeta production. Second, there is a surface-associated helix located at the cytosolic C-terminus, adjacent to the YENPTY motif that plays critical roles in APP trafficking and protein-protein interactions. Cholesterol was seen to participate in saturable interactions with C99 that are centered at the critical loop connecting the extracellular helix to the transmembrane domain. Binding of cholesterol to C99 and, most likely, to APP may be critical for the trafficking of these proteins to cholesterol-rich membrane domains, which leads to cleavage by beta- and gamma-secretase and resulting amyloid-beta production. It is proposed that APP may serve as a cellular cholesterol sensor that is linked to mechanisms for suppressing cellular cholesterol uptake.

  View details for DOI 10.1021/bi800993c

  View details for Web of Science ID 000258866700009

  View details for PubMedID 18702528

  View details for PubMedCentralID PMC2572687

• Substrate specificity of gamma-secretase and other intramembrane proteases CELLULAR AND MOLECULAR LIFE SCIENCES Beel, A. J., Sanders, C. R. 2008; 65 (9): 1311-1334

  Abstract

  Gamma-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the mechanistic basis of gamma-secretase proteolysis and the precise factors regulating substrate identification is important because modulation of this biochemical degradative process can have important consequences in a physiological and pathophysiological context. Here, we briefly review such information for all major classes of intramembranously cleaving proteases (I-CLiPs), with an emphasis on gamma-secretase, an I-CLiP closely linked to the etiology of Alzheimer's disease. A large body of emerging data allows us to survey the substrates of gamma-secretase to ascertain the conformational features that predispose a peptide to cleavage by this enigmatic protease. Because substrate specificity in vivo is closely linked to the relative subcellular compartmentalization of gamma-secretase and its substrates, we also survey the voluminous body of literature concerning the traffic of gamma-secretase and its most prominent substrate, the amyloid precursor protein.

  View details for DOI 10.1007/s00018-008-7462-2

  View details for Web of Science ID 000256099200003

  View details for PubMedID 18239854

  View details for PubMedCentralID PMC2569971