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Calcium-binding to apoptosis-linked ...

Subramanian, Lalita.

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Calcium-binding to apoptosis-linked gene-2 and its modulation in uveal melanoma.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Calcium-binding to apoptosis-linked gene-2 and its modulation in uveal melanoma./
Author:	Subramanian, Lalita.
Description:	127 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-05, Section: B, page: 2575.
Contained By:	Dissertation Abstracts International66-05B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3175519
ISBN:	9780542140952

Calcium-binding to apoptosis-linked gene-2 and its modulation in uveal melanoma.
Subramanian, Lalita.

Calcium-binding to apoptosis-linked gene-2 and its modulation in uveal melanoma. - 127 p.

Source: Dissertation Abstracts International, Volume: 66-05, Section: B, page: 2575.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2005.

Apoptosis-Linked Gene 2 (ALG-2) encodes a 22 kDa Ca 2+-binding protein of the penta EF-hand family that is required for programmed cell death in response to various apoptotic agents. Here, we demonstrate that ALG-2 mRNA and protein are down-regulated in human uveal melanoma cells compared to their progenitor cells, normal melanocytes. Further, ALG-2 and its putative target molecule, Alix/AIP1, are localized primarily in the cytoplasm of melanocytes and melanoma cells independent of [Ca2+]i or the activation of apoptosis. Also independent of [Ca2+], cross-linking and analytical centrifugation studies support a single-species dimer conformation of ALG-2. Ca2+-binding measurements using flow dialysis establish EF-1 and EF-3 as the high affinity Ca2+-binding sites. Ca2+-binding primarily to EF-3 causes an increase in surface hydrophobicity, underlying the development of the hydrophobic pocket observed in the crystal structure. However, surface plasmon resonance spectroscopy demonstrates that binding of Ca2+ to both EF-1 and EF-3 is necessary for ALG-2 interactions with target molecules. Deletion mutants and peptides derived from the N-terminal region of human ALG-2 suggest little involvement of this region on either the Ca2+ -induced conformational change or subsequent interactions, contrary to the model derived from the crystal structure of ALG-2. The amino acids lining the hydrophobic pocket, on the other hand, contribute significantly to the interactions of ALG-2 with target molecules. The down-regulation of ALG-2 may provide melanoma cells with a selective advantage, however, a direct correlation between ALG-2 levels and susceptibility of melanoma cells to apoptosis is yet to be observed. The studies presented here elucidate for the first time the impact on the exposure of hydrophobic surfaces as regions of target recognition as a result of Ca2+-binding to each of the high affinity sites in ALG-2.

ISBN: 9780542140952Subjects--Topical Terms:

1017719
Biology, Molecular.

Calcium-binding to apoptosis-linked gene-2 and its modulation in uveal melanoma.
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245 1 0 $a Calcium-binding to apoptosis-linked gene-2 and its modulation in uveal melanoma.
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520 $a Apoptosis-Linked Gene 2 (ALG-2) encodes a 22 kDa Ca 2+-binding protein of the penta EF-hand family that is required for programmed cell death in response to various apoptotic agents. Here, we demonstrate that ALG-2 mRNA and protein are down-regulated in human uveal melanoma cells compared to their progenitor cells, normal melanocytes. Further, ALG-2 and its putative target molecule, Alix/AIP1, are localized primarily in the cytoplasm of melanocytes and melanoma cells independent of [Ca2+]i or the activation of apoptosis. Also independent of [Ca2+], cross-linking and analytical centrifugation studies support a single-species dimer conformation of ALG-2. Ca2+-binding measurements using flow dialysis establish EF-1 and EF-3 as the high affinity Ca2+-binding sites. Ca2+-binding primarily to EF-3 causes an increase in surface hydrophobicity, underlying the development of the hydrophobic pocket observed in the crystal structure. However, surface plasmon resonance spectroscopy demonstrates that binding of Ca2+ to both EF-1 and EF-3 is necessary for ALG-2 interactions with target molecules. Deletion mutants and peptides derived from the N-terminal region of human ALG-2 suggest little involvement of this region on either the Ca2+ -induced conformational change or subsequent interactions, contrary to the model derived from the crystal structure of ALG-2. The amino acids lining the hydrophobic pocket, on the other hand, contribute significantly to the interactions of ALG-2 with target molecules. The down-regulation of ALG-2 may provide melanoma cells with a selective advantage, however, a direct correlation between ALG-2 levels and susceptibility of melanoma cells to apoptosis is yet to be observed. The studies presented here elucidate for the first time the impact on the exposure of hydrophobic surfaces as regions of target recognition as a result of Ca2+-binding to each of the high affinity sites in ALG-2.
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