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The Crystal Structure of the Influenza Matrix Protein M1 at Neutral Ph: M1–M1 Protein Interfaces Can Rotate in the Oligomeric Structures of M1

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The Crystal Structure of the Influenza Matrix Protein M1 at Neutral Ph: M1–M1 Protein Interfaces Can Rotate in the Oligomeric Structures of M1 Virology 289, 34–44 (2001) doi:10.1006/viro.2001.1119, available online at http://www.idealibrary.com on View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector The Crystal Structure of the Influenza Matrix Protein M1 at Neutral pH: M1–M1 Protein Interfaces Can Rotate in the Oligomeric Structures of M1 Audray Harris, Farhad Forouhar, Shihong Qiu, Bingdong Sha,1 and Ming Luo2 Department of Microbiology and Center for Biophysical Sciences and Engineering, University of Alabama at Birmingham, Birmingham, Alabama 35294 Received May 15, 2001; returned to author for revision July 9, 2001; accepted July 27, 2001 The influenza matrix protein (M1) forms a protein layer under the viral membrane and is essential for viral stability and integrity. M1 mediates the encapsidation of the viral RNPs into the viral membrane by its membrane and RNP-binding activities. In order to understand the roles of M1–M1 protein interactions in forming the M1 layer, X-ray crystallographic studies of a M1 fragment (1–162) were carried out at neutral pH and compared with an acidic pH structure. At neutral pH the asymmetric unit was a stacked dimer of M1. A long molecular ribbon of neutral stacked dimers was formed by translation as dictated by the P1 space group. The elongated ribbon had a positively charged stripe on one side of the ribbon. A similar M1–M1 stacking interface was also found in the acidic asymmetric unit. However, within the acidic stacked dimer the molecules were not straight, but rotated in relation to each other by slightly changing the M1–M1 stacking interface. The acidic structure possessed an additional M1–M1 twofold interface. Protein docking confirmed that the M1–M1 stacking and M1–M1 twofold interfaces could be used to form a double ribbon of M1 molecules. By iterative repetition of the rotated relationship among the M1 molecules, a helix of M1 was generated. These studies suggest that M1 has the ability to form straight or bent elongated ribbons and helices. These oligomers are consistent with previous electron microscopic studies of M1, which demonstrated that isolated M1 formed elongated and flexible ribbons when isolated from what appeared to be a helical shell of M1 in the influenza virus. © 2001 Academic Press Key Words: influenza matrix protein M1; M1 helix; protein–protein interactions; virus assembly. INTRODUCTION metries (Caspar and Klug, 1962). Intact icosahedral vi- ruses are often amendable to structural studies by X-ray Viruses have evolved a protein shell to protect their crystallography and cryoelectron microscopy (Johnson nucleic acids from extracellular and intracellular environ- and Chiu, 2000). In some cases, solving or crystallizing ments that would destroy the genetic material. The en- the intact virus is not possible because of the lack of high capsidation of the genetic material may involve a single symmetry. Therefore, individual components of the virus protein shell or multiple layers of protein coverings (John- are crystallized and the structures determined. The over- son and Chiu, 2000). These protein shells may aid in cell all structure of the virus could be deduced by building entry or be coated by a viral membrane that contains the virus with these subunit structures into the virion viral proteins required for entry (Marsh and Helenius, based on low-resolution structures produced by electron 1989). Protein shells are often referred to as nucleocap- microscopy. This is the case for polymorphic viruses sids, capsids, and matrix layers, and the evolutionary such as HIV (Wilk and Fuller, 1999; Li et al., 2000), and pressure to protect the genetic material leads to the use this strategy may be applied to other viruses such as the of symmetry-related redundant protein interactions in influenza virus. forming these protein layers (Crick et al., 1956). The use The influenza virus is also a polymorphic virus with of reoccurring protein interactions is an evolutionary multiple proteins bound to the eight segmented genomic advantage and limits the amount of nucleic acid neces- RNAs. Virus preparations may contain viruses with vary- sary for encoding the protective protein shell. The most ing sizes and shapes (Morgan et al., 1956; Choppin et al., common forms of redundancy for constructing viral pro- 1961; Hoyle et al., 1961; Compans and Dimmock, 1969). tein shells seem to employ icosahedral and helical sym- The virus consists of two layers of protein shells, the nucleocapsid protein (NP) and the matrix protein (M1), that assemble around and protect the genomic RNAs. 1 Current address: Department of Cell Biology, University of Alabama Assembly of the influenza virus consists of a number of at Birmingham, Birmingham, AL 35294. simultaneous steps that take place in different compart- 2 To whom correspondence and reprint requests should be ad- dressed at The University of Alabama at Birmingham, 262 McCallum ments of the cell (Lamb and Krug, 1996). The compart- Basic Health Sciences Building, 1918 University Boulevard, Birming- mentalization mechanism of the host cell is employed to ham, AL 35294-0005. Fax: (205) 975-9578. E-mail: [email protected]. direct the insertion of the viral proteins hemagglutinin 0042-6822/01 $35.00 Copyright © 2001 by Academic Press 34 All rights of reproduction in any form reserved. THE NEUTRAL STRUCTURE OF M1 35 (HA), neuraminidase (NA), and M2 into the cellular mem- TABLE 1 brane. In the nucleus, the replicated genomic RNAs Data Collection and Refinement Statistics along with the polymerase complex are coated with NP to form RNA nucleoproteins (RNPs) (Pons et al., 1969; Resolution 25–2.15 (2.25–2.15) Å Honda et al., 1988). With a nucleation signal, M1 protein Observations 26,469 (1975) acts as an adapter molecule by having dual activities: a Unique reflections 14,801 (1506) Completeness (%) 94.1 (81.7) membrane-binding activity and a RNP-binding activity (Ye ͗I͘/͗␴I͘ 18.3 (5.89) et al., 1987, 1989; Wakefield and Brownlee, 1989; Bucher R merge (%) 10.8 (20.2) et al., 1980). The membrane-binding activity allows M1 to Crystal system Triclinic be accumulated at and bound to the cellular membrane Space group P1 ϭ ϭ ϭ where HA and NA have been embedded. At the same Unit cell a 36.300, b 44.651, c 48.140 Å ␣ ϭ 96.344, ␤ ϭ 111.071, ␥ ϭ 102.579° time, the RNP-binding activity allows M1 to bind to RNPs Asymmetric unit M1 dimer (unit cell contents) in the nucleus and assist in their export to the cytoplasm R factor (%) 0.2250 (Whittaker et al., 1996; O’Neill et al., 1998). Additional M1 R free (%) 0.2679 molecules bind to the exported RNPs and transport them Bond length deviation 0.011 Å to the cellular membrane where membrane-bound M1 is Bond angle deviation 1.92° located, and this is followed by the pinching off of the N Note. R merge ϭ ¥ hkl ¥ Jϭ1͉I hkl Ϫ I hkl( j)͉/¥ hkl NXIhkl. R merge compares N virus from the cell surface. These combined events of data sets after merging. I hkl is the intensity of an individual measure- ϭ ¥ ͉͉ ͉ Ϫ ͉ ͉ assembly result in a viral particle in which the RNA ment of the reflection with indices hkl. R factor hkl F obs k F calc / ¥ ͉ ͉ genome is complexed with NP and surrounded by a layer hkl F obs . The crystallographic R factor indicates the correctness of a of M1 that is underneath the viral membrane containing model protein structure. It gives a measure of the closeness of a built atomic model to the collected diffraction data. F are the observed HA, NA, and M2. M1 is required for the association obs structure factor amplitudes from the diffraction data. F calc are the cal- between the membrane and RNPs. culated structure factor amplitudes from the model protein structure. ϭ ¥ ͉͉ ͉ Ϫ ͉ ͉͉ ¥ ͉ ͉ The aims of this study were to examine the roles of R Tfree hklʚT F obs k F calc / hklʚT F obs . All reflections belonging to M1–M1 interactions in forming oligomeric states of M1 the test set T of unique reflections is given by hkl ʚ T. Refinement is and to understand how these oligomeric states may form carried out with the remaining reflections, the working set W. a M1 layer. We determined the structure of M1 at pH 7.0, which is close to physiological pH at which virus parti- to that of the acidic structure (Fig. 1). The molecule ␣ cles form. We compared and contrasted the neutral consists of eight -helices (H1–H4, H6–H9) and a 310 structure with a previous solved structure of M1 at pH helix H5. The protein fragment can be divided into an N 4.0. M1 oligomers and atomic protein interactions were domain consisting of H1–H4 and an M domain consist- also evaluated. In addition, protein-docking experiments ing of H6–H9. Flexible loops in four regions are the main were carried out to simulate M1 molecules binding to differences between neutral and acidic monomers. The one another. Computer-simulated repetition of a specific root-mean-square deviation (RMSD) of the C␣ positions M1–M1 binding pattern generated a M1 supra-oligomer between the superimposed neutral and acidic mono- of a helix. The observed forms of M1 oligomers and the mers is 1.2 Å (Fig. 1). It seems that the RMSD is in- M1–M1 interaction sites are consistent with M1 struc- creased due to the change in the position of these tures visible by electron microscopy. flexible loops. Amino acids 70–76, which connect H4 with H5, are disordered in the electron density map of the RESULTS neutral structure (Fig.
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