Evolutionary and physical linkage between calpains and penta‐EF‐hand Ca<sup>2+</sup>‐binding proteins

Maki, Masatoshi; Maemoto, Yuki; Osako, Yohei; Shibata, Hideki

doi:10.1111/j.1742-4658.2012.08560.x

Cited by 34 publications

(36 citation statements)

References 49 publications

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“…This promotes the release of virion particles (9) with the help of AAA-ATPase VPS4B (vacuolar protein sorting 4 homolog B) (10,11). The penta-EF-hand protein ALG-2 (apoptosis-linked gene-2, also known as PDCD6) participates in the process by interacting with both ALIX (12,13) and TSG101 (14) in a calcium-dependent manner and bridges ESCRT-III and ESCRT-I through dimerization (15)(16)(17). However, the function of ALG-2 in viral replication, especially that of HIV-1, remains unknown.…”

mentioning

confidence: 99%

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Zhang²,

Feng

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerIn the HIV-1 replication cycle, the endosomal sorting complex required for transport (ESCRT) machinery promotes viral budding and release in the late stages. In this process, the ESCRT proteins, ALIX and TSG101, are recruited through interactions with HIV-1 Gag p6. ALG-2, also known as PDCD6, interacts with both ALIX and TSG101 and bridges ESCRT-III and ESCRT-I. In this study, we show that ALG-2 affects HIV-1 production negatively at both the exogenous and endogenous levels. Through a yeast two-hybrid screen, we identified HEBP2 as the binding partner of ALG-2, and we solved the crystal structure of the ALG-2⅐HEBP2 complex. The function of ALG-2⅐HEBP2 complex in HIV-1 replication was further explored. ALG-2 inhibits HIV-1 production by affecting Gag expression and distribution, and HEBP2 might aid this process by tethering ALG-2 in the cytoplasm.The endosomal sorting complex required for transport (ESCRT) 3 machinery functions in HIV-1 budding and release in the late stages of viral replication (1-3). In this process, ALIX (ALG-2 interacting protein X) and TSG101 (tumor susceptibility gene 101), components of ESCRT-III and ESCRT-I, are recruited to the budding site of HIV-1 through interactions with HIV-1 Gag p6 (4 -8). This promotes the release of virion particles (9) with the help of AAA-ATPase VPS4B (vacuolar protein sorting 4 homolog B) (10, 11). The penta-EF-hand protein ALG-2 (apoptosis-linked gene-2, also known as PDCD6) participates in the process by interacting with both ALIX (12, 13) and TSG101 (14) in a calcium-dependent manner and bridges ESCRT-III and ESCRT-I through dimerization (15)(16)(17). However, the function of ALG-2 in viral replication, especially that of HIV-1, remains unknown.ALG-2 was first identified in a functional screen for anti-apoptotic proteins involved in T-cell receptor, Fas, and glucocorticoid-induced cell death (18). It was defined as a proapoptotic molecule because expression of its antisense strand led to rescue from cell death (19). However, ALG-2 knock-out mice are viable and exhibit normal T-cell development (20), which suggested that other redundant proteins might exist in mammalian cells. ALG-2 is a penta-EF-hand protein (13, 15), containing five repeats of the EF-hand motif, and coordinates three calcium ions via EF1, EF3, and EF5. However, the coordination of calcium by EF5 is weak and may be physiologically unimportant. ALG-2 exists as a dimer, which might be critical for its function as an adaptor molecule in signal transduction (15). ALG-2 can interact with dozens of proteins through several pockets (pockets 1-3) on its molecular surface. The binding motif for ALG-2, designated as the ALG-2-binding site (ABS), is a short sequence rich in Pro, Gly, and Tyr. Two typical ABS sequences have been described. ABS-1, which is represented as PPYPXXPGYP (X represents any residue) and occupies pocket 1 on the ALG-2 surface, is found in ALIX and PLSCR3 (6), whereas ABS-2, containing a PXPGF sequence that binds pocket 3, is found in SEC31 and PLSCR3 (1...

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confidence: 99%

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Zhang²,

Feng

et al. 2016

Journal of Biological Chemistry

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“…Recently solved structures, e.g. that of the protease calpain (20), have indicated that the functional motifs of these proteins occur in pairs, either by homodimerization or by heterodimerization, whereas the non-functional fifth EF-hand acts as a dimerization domain.…”

Section: Calcium Binding and Sensor Proteins The Ef-handmentioning

confidence: 99%

Why Calcium? How Calcium Became the Best Communicator

Carafoli

Krebs

2016

Journal of Biological Chemistry

312

213

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Calcium carries messages to virtually all important functions of cells. Although it was already active in unicellular organisms, its role became universally important after the transition to multicellular life. In this Minireview, we explore how calcium ended up in this privileged position. Most likely its unique coordination chemistry was a decisive factor as it makes its binding by complex molecules particularly easy even in the presence of large excesses of other cations, e.g. magnesium. Its free concentration within cells can thus be maintained at the very low levels demanded by the signaling function. A large cadre of proteins has evolved to bind or transport calcium. They all contribute to buffer it within cells, but a number of them also decode its message for the benefit of the target. The most important of these "calcium sensors" are the EF-hand proteins. Calcium is an ambivalent messenger. Although essential to the correct functioning of cell processes, if not carefully controlled spatially and temporally within cells, it generates variously severe cell dysfunctions, and even cell death.At the beginning, life on earth consisted of single cells that were capable of carrying out all vital functions. The interplay with other cells was largely limited to the competition for nutrients. Unicellularity was clearly successful, as shown by the fact that unicellular organisms are actually still predominant today. Nevertheless, at a time which was generally estimated to be at 600 -700 million years ago, but which is now being pushed back to more than 2 billion years ago (1, 2), competition was replaced by cooperation, and multicellular life evolved. It had somehow become advantageous for cells to work together rather than to live alone. Cells became gradually organized into structures in which they learned to perform different tasks and to cooperate in the division of labor. Cooperation naturally demanded the communication of cells with each other, i.e. it demanded the development of agents that could exchange messages between cells. As the complexity of the multicellular organization increased, so did the number of cells with distinct functional tasks. The number of intercellular signaling molecules and the degree of their complexity increased in parallel. A basic tenet of life is regulation. Thus, all vital functions within the cells are regulated. Indeed, they are also regulated in unicellular organisms. However, the transition to multicellular life brought with it the intercellular exchange of messages as an additional, and essential, regulation category.Calcium, the third most abundant metal in nature, was amply available to cells from the beginning, and was adopted as a regulator at an early evolutionary stage. The basic principles of calcium regulation were already present in prokaryotes and protists (3, 4), but calcium regulation gradually grew to cover nearly all aspects of cell function after the transition to multicellularity. Naturally, agents that carry messages to intracellular targets must be maint...

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“…1,2) Although ALG-2 was originally identified as a pro-apoptotic protein in Tcell hybridoma, 3) ALG-2 knockout mice developed normally with no obvious abnormalities in the immune system. 4) Nonetheless, accumulating data suggest the involvement of ALG-2 in apoptosis, cell cycle, signal transduction, and cancer.…”

Section: Alg-2 Is An Ef-hand-type Camentioning

confidence: 99%

Mammalian ESCRT-III-Related Protein IST1 Has a Distinctive Met-Pro Repeat Sequence That Is Essential for Interaction with ALG-2 in the Presence of Ca²⁺

Okumura

Takahashi

Shibata

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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Evolutionary and physical linkage between calpains and penta‐EF‐hand Ca²⁺‐binding proteins

Cited by 34 publications

References 49 publications

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Why Calcium? How Calcium Became the Best Communicator

Mammalian ESCRT-III-Related Protein IST1 Has a Distinctive Met-Pro Repeat Sequence That Is Essential for Interaction with ALG-2 in the Presence of Ca²⁺

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Evolutionary and physical linkage between calpains and penta‐EF‐hand Ca2+‐binding proteins

Cited by 34 publications

References 49 publications

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Structural and Functional Study of Apoptosis-linked Gene-2·Heme-binding Protein 2 Interactions in HIV-1 Production

Why Calcium? How Calcium Became the Best Communicator

Mammalian ESCRT-III-Related Protein IST1 Has a Distinctive Met-Pro Repeat Sequence That Is Essential for Interaction with ALG-2 in the Presence of Ca2+

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Evolutionary and physical linkage between calpains and penta‐EF‐hand Ca²⁺‐binding proteins

Mammalian ESCRT-III-Related Protein IST1 Has a Distinctive Met-Pro Repeat Sequence That Is Essential for Interaction with ALG-2 in the Presence of Ca²⁺