1qwh: Difference between revisions

Line 1:

[[Image:1qwh.gif|left|200px]]<br />

[[Image:1qwh.gif|left|200px]]<br /><applet load="1qwh" size="350" color="white" frame="true" align="right" spinBox="true"

<applet load="1qwh" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

caption="1qwh, resolution 1.36Å" />

'''a covalent dimer of transthyretin that affects the amyloid pathway'''<br />

==Overview==

The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo, rate-limiting dissociation to partially denatured monomers in order to, aggregate. TTR contains two distinct quaternary interfaces, one of which, defines the binding sites for thyroxine and small-molecule amyloidogenesis, inhibitors. Kinetic stabilization of the tetramer can be accomplished, either by the binding of amyloidogenesis inhibitors selectively to the, native state over the dissociative transition state or by the introduction, of trans-suppressor subunits (T119M) into heterotetramers to destabilize, the dissociative transition state. In each case, increasing the, dissociation activation barrier prevents tetramer dissociation. Herein, we, demonstrate that tethering two subunits whose quaternary interface defines, the thyroxine binding site also dramatically increases the barrier for, tetramer dissociation, apparently by destabilization of the dissociative, transition state. The tethered construct (TTR-L-TTR)2 is structurally and, functionally equivalent to wild-type TTR. Urea is unable to denature, (TTR-L-TTR)2, yet it is able to maintain the denatured state once, denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2, is kinetically rather than thermodynamically stabilized, consistent with, the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves., Studies focused on a construct containing a single TTR-L-TTR chain and two, normal monomer subunits establish that alteration of only one quaternary, structural interface is sufficient to impose kinetic stabilization on the, entire quaternary structure.

The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo rate-limiting dissociation to partially denatured monomers in order to aggregate. TTR contains two distinct quaternary interfaces, one of which defines the binding sites for thyroxine and small-molecule amyloidogenesis inhibitors. Kinetic stabilization of the tetramer can be accomplished either by the binding of amyloidogenesis inhibitors selectively to the native state over the dissociative transition state or by the introduction of trans-suppressor subunits (T119M) into heterotetramers to destabilize the dissociative transition state. In each case, increasing the dissociation activation barrier prevents tetramer dissociation. Herein, we demonstrate that tethering two subunits whose quaternary interface defines the thyroxine binding site also dramatically increases the barrier for tetramer dissociation, apparently by destabilization of the dissociative transition state. The tethered construct (TTR-L-TTR)2 is structurally and functionally equivalent to wild-type TTR. Urea is unable to denature (TTR-L-TTR)2, yet it is able to maintain the denatured state once denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2 is kinetically rather than thermodynamically stabilized, consistent with the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves. Studies focused on a construct containing a single TTR-L-TTR chain and two normal monomer subunits establish that alteration of only one quaternary structural interface is sufficient to impose kinetic stabilization on the entire quaternary structure.

==Disease==

Line 11:

Line 10:

==About this Structure==

1QWH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1QWH OCA].

1QWH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QWH OCA].

==Reference==

Line 18:

Line 17:

[[Category: Single protein]]

[[Category: Foss, T.]]

[[Category: Kelker, M.S.]]

[[Category: Kelker, M S.]]

[[Category: Wilson, I.A.]]

[[Category: Wilson, I A.]]

[[Category: binding protein]]

[[Category: cerebrospinal fluid]]

Line 32:

Line 31:

[[Category: transport]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Mon Nov 12 18~~:57:~~05 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:44:28 2008''

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools

@@ Line 1: / Line 1: @@
-[[Image:1qwh.gif|left|200px]]<br />
+[[Image:1qwh.gif|left|200px]]<br /><applet load="1qwh" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1qwh" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1qwh, resolution 1.36&Aring;" />
 '''a covalent dimer of transthyretin that affects the amyloid pathway'''<br />
 ==Overview==
-The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo, rate-limiting dissociation to partially denatured monomers in order to, aggregate. TTR contains two distinct quaternary interfaces, one of which, defines the binding sites for thyroxine and small-molecule amyloidogenesis, inhibitors. Kinetic stabilization of the tetramer can be accomplished, either by the binding of amyloidogenesis inhibitors selectively to the, native state over the dissociative transition state or by the introduction, of trans-suppressor subunits (T119M) into heterotetramers to destabilize, the dissociative transition state. In each case, increasing the, dissociation activation barrier prevents tetramer dissociation. Herein, we, demonstrate that tethering two subunits whose quaternary interface defines, the thyroxine binding site also dramatically increases the barrier for, tetramer dissociation, apparently by destabilization of the dissociative, transition state. The tethered construct (TTR-L-TTR)2 is structurally and, functionally equivalent to wild-type TTR. Urea is unable to denature, (TTR-L-TTR)2, yet it is able to maintain the denatured state once, denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2, is kinetically rather than thermodynamically stabilized, consistent with, the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves., Studies focused on a construct containing a single TTR-L-TTR chain and two, normal monomer subunits establish that alteration of only one quaternary, structural interface is sufficient to impose kinetic stabilization on the, entire quaternary structure.
+The amyloidogenic homotetrameric protein transthyretin (TTR) must undergo rate-limiting dissociation to partially denatured monomers in order to aggregate. TTR contains two distinct quaternary interfaces, one of which defines the binding sites for thyroxine and small-molecule amyloidogenesis inhibitors. Kinetic stabilization of the tetramer can be accomplished either by the binding of amyloidogenesis inhibitors selectively to the native state over the dissociative transition state or by the introduction of trans-suppressor subunits (T119M) into heterotetramers to destabilize the dissociative transition state. In each case, increasing the dissociation activation barrier prevents tetramer dissociation. Herein, we demonstrate that tethering two subunits whose quaternary interface defines the thyroxine binding site also dramatically increases the barrier for tetramer dissociation, apparently by destabilization of the dissociative transition state. The tethered construct (TTR-L-TTR)2 is structurally and functionally equivalent to wild-type TTR. Urea is unable to denature (TTR-L-TTR)2, yet it is able to maintain the denatured state once denaturation is achieved by GdnHCl treatment, suggesting that (TTR-L-TTR)2 is kinetically rather than thermodynamically stabilized, consistent with the identical wild-type TTR and (TTR-L-TTR)2 GdnHCl denaturation curves. Studies focused on a construct containing a single TTR-L-TTR chain and two normal monomer subunits establish that alteration of only one quaternary structural interface is sufficient to impose kinetic stabilization on the entire quaternary structure.
 ==Disease==
@@ Line 11: / Line 10: @@
 ==About this Structure==
-QWH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1QWH OCA].
+QWH is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QWH OCA].
 ==Reference==
@@ Line 18: / Line 17: @@
 [[Category: Single protein]]
 [[Category: Foss, T.]]
-[[Category: Kelker, M.S.]]
+[[Category: Kelker, M S.]]
-[[Category: Wilson, I.A.]]
+[[Category: Wilson, I A.]]
 [[Category: binding protein]]
 [[Category: cerebrospinal fluid]]
@@ Line 32: / Line 31: @@
 [[Category: transport]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:57:05 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:44:28 2008''