The mechanism of Ca2+-dependent recognition of Alix by ALG-2: insights from X-ray crystal structures

2009 ◽  
Vol 37 (1) ◽  
pp. 190-194 ◽  
Author(s):  
Hironori Suzuki ◽  
Masato Kawasaki ◽  
Tatsutoshi Inuzuka ◽  
Mayumi Okumura ◽  
Takeshi Kakiuchi ◽  
...  
Keyword(s):  
Tandem Repeats ◽  
Susceptibility Gene ◽  
Adaptor Protein ◽  
Side Chain ◽  
Interacting Protein ◽  
Linked Gene ◽  
X Ray ◽  
Ef Hand ◽  
Peptide Binding Site ◽  
Crystal Structural

Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X] was originally identified as a protein that interacts with ALG-2, a member of the penta-EF-hand Ca2+-binding protein family. ALG-2 binds to its C-terminal proline-rich region that contains four tandem repeats of PXY (where X represents an uncharged amino acid). Recent X-ray crystal structural analyses of the Ca2+-free and Ca2+-bound forms of ALG-2, as well as the complex with an Alix oligopeptide, have revealed a mechanism of Ca2+-dependent binding of ALG-2 to its target protein. Binding of Ca2+ to EF3 (third EF-hand) enables the side chain of Arg125, present in the loop connecting EF3 and EF4 (fourth EF-hand), to move sufficiently to make a primary hydrophobic pocket accessible to the critical PPYP (Pro-Pro-Tyr-Pro) motif in Alix, which partially overlaps with the GPP (Gly-Pro-Pro) motif for binding to Cep55 (centrosome protein of 55 kDa). The fact that ALG-2 forms a homodimer and each monomer has one peptide-binding site indicates the possibility that ALG-2 bridges two interacting proteins, including Alix and Tsg101 (tumour susceptibility gene 101), and functions as a Ca2+-dependent adaptor protein.

The ESCRT pathway and HIV-1 budding

2009 ◽  
Vol 37 (1) ◽  
pp. 181-184 ◽  
Author(s):  
Yoshiko Usami ◽  
Sergei Popov ◽  
Elena Popova ◽  
Michio Inoue ◽  
Winfried Weissenhorn ◽  
...  
Keyword(s):  
Susceptibility Gene ◽  
Multivesicular Body ◽  
Intramolecular Interactions ◽  
Transport Pathway ◽  
Interacting Protein ◽  
Linked Gene ◽  
Endosomal Sorting ◽  
Binding Partner ◽  
Protein X ◽  
Hiv 1

HIV-1 Gag engages components of the ESCRT (endosomal sorting complex required for transport) pathway via so-called L (late-assembly) domains to promote virus budding. Specifically, the PTAP (Pro-Thr-Ala-Pro)-type primary L domain of HIV-1 recruits ESCRT-I by binding to Tsg101 (tumour susceptibility gene 101), and an auxiliary LYPXnL (Leu-Tyr-Pro-Xaan-Leu)-type L domain recruits the ESCRT-III-binding partner Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X]. The structurally related CHMPs (charged multivesicular body proteins), which form ESCRT-III, are kept in an inactive state through intramolecular interactions, and become potent inhibitors of HIV-1 budding upon removal of an autoinhibitory region. In the absence of the primary L domain, HIV-1 budding is strongly impaired, but can be efficiently rescued through the overexpression of Alix. This effect of Alix depends on its ability to interact with CHMP4, suggesting that it is the recruitment of CHMPs that ultimately drives virus release. Surprisingly, HIV-1 budding defects can also be efficiently corrected by overexpressing Nedd (neural-precursor-cell-expressed developmentally down-regulated) 4-2s, a member of a family of ubiquitin ligases previously implicated in the function of PPXY (Pro-Pro-Xaa-Tyr)-type L domains, which are absent from HIV-1. At least under certain circumstances, Nedd4-2s stimulates the activity of PTAP-type L domains, raising the possibility that the ubiquitin ligase regulates the activity of ESCRT-I.

scholarly journals The Adaptor Protein Alix is Involved in the Interaction Between the Ubiquitin Ligase NEDD4-1 and its Targets, ABCG1 and ABCG4

2019 ◽  
Vol 20 (11) ◽  
pp. 2714 ◽  
Author(s):  
Amjad Alrosan ◽  
Shereen M. Aleidi ◽  
Alryel Yang ◽  
Andrew J. Brown ◽  
Ingrid C. Gelissen
Keyword(s):  
Ubiquitin Ligase ◽  
Abc Transporters ◽  
Adaptor Protein ◽  
Interacting Protein ◽  
Linked Gene ◽  
Transporter Protein ◽  
Peptide Mass ◽  
Protein X ◽  
Peptide Mass Spectrometry ◽  
Gene 4

Several ATP-Binding Cassette (ABC) transporters, including ABCG1 and the related ABCG4, are essential regulators of cellular lipid homeostasis. ABCG1 is expressed ubiquitously and is functional in the context of atherosclerosis. However, ABCG4 is expressed almost exclusively in brain and has been linked to Alzheimer’s disease (AD). These transporters are highly regulated post-translationally by E3 ubiquitin ligases, with the ligase NEDD4-1 (Neural precursor cell-expressed developmentally downregulated gene 4) implicated in their protein stability. In this study, we investigated interacting partners of ABCG1 using peptide-mass spectrometry and identified the potential adaptor protein, Alix (apoptosis-linked gene 2-interacting protein X). In this paper, we hypothesized and investigated whether Alix could facilitate the interaction between NEDD4-1 and the ABC transporters. We showed that Alix and NEDD4-1 proteins were co-expressed in several commonly used cell lines. Knockdown of Alix in cells overexpressing ABCG1 or ABCG4 increased transporter protein expression while co-immunoprecipitation experiments showed interaction between NEDD4-1, Alix, and ABC transporters. In summary, we provide evidence that Alix serves as a co-factor for the interaction between the E3-ubiquitin ligase NEDD4-1 and the ABC transporter targets, ABCG1 and ABCG4.

Alix and ALG-2 make a link between endosomes and neuronal death

2009 ◽  
Vol 37 (1) ◽  
pp. 200-203 ◽  
Author(s):  
Anne-Laure Mahul-Mellier ◽  
Flavie Strappazzon ◽  
Christine Chatellard-Causse ◽  
Béatrice Blot ◽  
David Béal ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Calcium Binding ◽  
Death Receptor ◽  
Adaptor Protein ◽  
Endosomal Trafficking ◽  
Interacting Protein ◽  
Linked Gene ◽  
Endosomal Sorting ◽  
Factor Α ◽  
Necrosis Factor

Alix [ALG-2 (apoptosis-linked gene 2)-interacting protein X] is a ubiquitinous adaptor protein first described for its capacity to bind to the calcium-binding protein, ALG-2. Alix regulates neuronal death in ways involving interactions with ALG-2 and with proteins of the ESCRT (endosomal sorting complex required for transport). Even though all Alix interactors characterized to date are involved in endosomal trafficking, the genuine function of the protein in this process remains unclear. We have demonstrated recently that Alix and ALG-2 form in the presence of calcium, a complex with apical caspases and with the endocytosed death receptor TNFR1 (tumour necrosis factor α receptor 1), thus suggesting a molecular coupling between endosomes and the cell death machinery.

scholarly journals Synthesis of New Derivatives of BEDT-TTF: Installation of Alkyl, Ethynyl, and Metal-Binding Side Chains and Formation of Tris(BEDT-TTF) Systems

2021 ◽  
Vol 7 (8) ◽  
pp. 110
Author(s):  
Songjie Yang ◽  
Matteo Zecchini ◽  
Andrew Brooks ◽  
Sara Krivickas ◽  
Desiree Dalligos ◽  
...  
Keyword(s):  
Metal Binding ◽  
Tricarboxylic Acid ◽  
Metal Salts ◽  
Side Chain ◽  
Side Chains ◽  
Ethynyl Group ◽  
X Ray ◽  
Transition Metal Salts ◽  
Alkyl Side Chains ◽  
Derivatives Of

The syntheses of new BEDT-TTF derivatives are described. These comprise BEDT-TTF with one ethynyl group (HC≡C-), with two (n-heptyl) or four (n-butyl) alkyl side chains, with two trans acetal (-CH(OMe)2) groups, with two trans aminomethyl (-CH2NH2) groups, and with an iminodiacetate (-CH2N(CH2CO2−)2 side chain. Three transition metal salts have been prepared from the latter donor, and their magnetic properties are reported. Three tris-donor systems are reported bearing three BEDT-TTF derivatives with ester links to a core derived from benzene-1,3,5-tricarboxylic acid. The stereochemistry and molecular structure of the donors are discussed. X-ray crystal structures of two BEDT-TTF donors are reported: one with two CH(OMe)2 groups and with one a -CH2N(CH2CO2Me)2 side chain.

scholarly journals Arsenoplatin-Ferritin Nanocage: Structure and Cytotoxicity

2021 ◽  
Vol 22 (4) ◽  
pp. 1874
Author(s):  
Giarita Ferraro ◽  
Alessandro Pratesi ◽  
Damiano Cirri ◽  
Paola Imbimbo ◽  
Daria Maria Monti ◽  
...  
Keyword(s):  
Biological Activity ◽  
Diffraction Data ◽  
Inductively Coupled Plasma ◽  
Emission Spectroscopy ◽  
Atomic Emission ◽  
Side Chain ◽  
Plasma Atomic Emission ◽  
Average Amount ◽  
X Ray ◽  
Inductively Coupled

Arsenoplatin-1 (AP-1), the prototype of a novel class of metallodrugs containing a PtAs(OH)2 core, was encapsulated within the apoferritin (AFt) nanocage. UV-Vis absorption spectroscopy and inductively coupled plasma-atomic emission spectroscopy measurements confirmed metallodrug encapsulation and allowed us to determine the average amount of AP-1 trapped inside the cage. The X-ray structure of AP-1-encapsulated AFt was solved at 1.50 Å. Diffraction data revealed that an AP-1 fragment coordinates the side chain of a His residue. The biological activity of AP-1-loaded AFt was comparatively tested on a few representative cancer and non-cancer cell lines. Even though the presence of the cage reduces the overall cytotoxicity of AP-1, it improves its selectivity towards cancer cells.

scholarly journals The Novel Adaptor Protein, Mti1p, and Vrp1p, a Homolog of Wiskott-Aldrich Syndrome Protein-Interacting Protein (WIP), May Antagonistically Regulate Type I Myosins in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 160 (3) ◽  
pp. 923-934
Author(s):  
Junko Mochida ◽  
Takaharu Yamamoto ◽  
Konomi Fujimura-Kamada ◽  
Kazuma Tanaka
Keyword(s):  
Adaptor Protein ◽  
Actin Binding ◽  
Temperature Sensitive ◽  
Null Mutation ◽  
Type I ◽  
Cortical Actin ◽  
Tail Region ◽  
Interacting Protein ◽  
Wiskott Aldrich Syndrome ◽  
Syndrome Protein

Abstract Type I myosins in yeast, Myo3p and Myo5p (Myo3/5p), are involved in the reorganization of the actin cytoskeleton. The SH3 domain of Myo5p regulates the polymerization of actin through interactions with both Las17p, a homolog of mammalian Wiskott-Aldrich syndrome protein (WASP), and Vrp1p, a homolog of WASP-interacting protein (WIP). Vrp1p is required for both the localization of Myo5p to cortical patch-like structures and the ATP-independent interaction between the Myo5p tail region and actin filaments. We have identified and characterized a new adaptor protein, Mti1p (Myosin tail region-interacting protein), which interacts with the SH3 domains of Myo3/5p. Mti1p co-immunoprecipitated with Myo5p and Mti1p-GFP co-localized with cortical actin patches. A null mutation of MTI1 exhibited synthetic lethal phenotypes with mutations in SAC6 and SLA2, which encode actin-bundling and cortical actin-binding proteins, respectively. Although the mti1 null mutation alone did not display any obvious phenotype, it suppressed vrp1 mutation phenotypes, including temperature-sensitive growth, abnormally large cell morphology, defects in endocytosis and salt-sensitive growth. These results suggest that Mti1p and Vrp1p antagonistically regulate type I myosin functions.

Are mesoionic compounds aromatic?

1998 ◽  
Vol 76 (6) ◽  
pp. 869-872 ◽  
Author(s):  
Alfredo Mayall Simas ◽  
Joseph Miller ◽  
Petrônio Filgueiras de Athayade Filho
Keyword(s):  
Experimental Evidence ◽  
Key Words ◽  
Dipole Moments ◽  
The Other ◽  
Side Chain ◽  
Theoretical Studies ◽  
X Ray Diffraction ◽  
Ring Plane ◽  
X Ray ◽  
Single Bonds

We have evaluated the experimental evidence relevant to the structure and character of mesoionic compounds, accumulated for more than 100 years and including X-ray diffraction studies. We have also evaluated relevant theoretical studies. All these, including our own extensive work, lead us to conclude that mesoionic compounds are not aromatic. According to our recent definition “mesoionic compounds are planar five-membered heterocyclic betaines with at least one side chain whose α-atom is also in the ring plane and with dipole moments of the order of 5 D. Electrons are delocalized over two regions separated by what are essentially single bonds. One region, which includes the a-atom of the side chain is associated with the HOMO and negative π-charge whereas the other is associated with the LUMO and positive π-charge.” Key words: mesoionic compounds, betaines, aromaticity.

X-ray powder diffraction data for ertapenem side chain, C20H19N3O7S

2017 ◽  
Vol 32 (3) ◽  
pp. 203-205
Author(s):  
Xiang Lin ◽  
Wei Ling Zhuo ◽  
Qiao Hong Du ◽  
Xi Lin Peng ◽  
Hui Li
Keyword(s):  
Powder Diffraction ◽  
Diffraction Data ◽  
Unit Cell Volume ◽  
Unit Cell ◽  
Side Chain ◽  
Powder Diffraction Data ◽  
Unit Cell Parameters ◽  
Space Group ◽  
X Ray ◽  
Cell Parameters

X-ray powder diffraction data, unit-cell parameters, and space group for ertapenem side chain, C20H19N3O7S, are reported [a = 4.907(6) Å, b = 18.686(3) Å, c = 22.071(1) Å, α = γ = 90°, β = 90.759(5)°, unit-cell volume V = 2023.82 Å3, Z = 4, ρcal = 1.462 g cm−3, and space group P21/c]. All measured lines were indexed and are consistent with the P21/c space group. No detectable impurity was observed.

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