Why am I posting this?
Well, I certainly don't expect a single person to understand it! (Definitely not me.) So that is not a reason.
What can we do about what is discussed? Pretty much nothing without understanding and without help and support.
It is to show that research is continuing, This does seem to provide some fundamental understanding of what T3 does at a molecular level - and how that affects cells - and our bodies.
To maintain hope that the biological activity of thyroid hormones will get fully recognised. And that will end up confirming many of the symptoms identified by those who know their thyroid hormones levels are raised, lowered, or variable.
Trying to be clear, this is just the effect of T3 on one binding site. Don't assume this is the only way in which T3 affects us.
Triiodothyronine Acts as a Smart Influencer on Hsp90 via a Triiodothyronine Binding Site
Lu Fan,
Athanasia Warnecke
Julia Weder
Matthias Preller
3,and Carsten Zeilinger
1 BMWZ (Zentrum für Biomolekulare Wirkstoffe), Gottfried-Wilhelm-Leibniz University of Hannover, Schneiderberg 38, 30167 Hannover, Germany
2 Department for Otorhinolaryngology—Head and Neck Surgery, Hannover Medical School (MHH), 30625 Hannover, Germany
3 Institute for Biophysical Chemistry, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
4 Institute for Functional Gene Analytics (IFGA), University of Applied Sciences Bonn-Rhein-Sieg, Von-Liebig-Str. 20, 53359 Rheinbach, Germany
Int. J. Mol. Sci. 2022, 23(13), 7150; doi.org/10.3390/ijms23137150
Received: 23 May 2022/ Revised: 20 June 2022/ Accepted: 24 June 2022/ Published: 28 June 2022
(This article belongs to the Section Molecular Biology)
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Abstract
Microarray-based experiments revealed that thyroid hormone triiodothyronine (T3) enhanced the binding of Cy5-labeled ATP on heat shock protein 90 (Hsp90). By molecular docking experiments with T3 on Hsp90, we identified a T3 binding site (TBS) near the ATP binding site on Hsp90. A synthetic peptide encoding HHHHHHRIKEIVKKHSQFIGYPITLFVEKE derived from the TBS on Hsp90 showed, in MST experiments, the binding of T3 at an EC50 of 50 μM. The binding motif can influence the activity of Hsp90 by hindering ATP accessibility or the release of ADP.
Keywords: triiodothyronine; Hsp90; protein microarray; thermophoresis; molecular docking
3. Discussion
The TBS on Hsp90 is special because it can act as a helix-turn-beta motif. These structures are often found in transcription factors and other highly regulated proteins. This would be an additional way to indirectly modulate Hsp90 by either fixing ATP or preventing its release and would thus give access to many proteins that are folded by Hsp90 [12]. This influence may become relevant to the high T3 concentrations or variety of chemicals in an environment with T3 activity. The cell physiological adjustment to T3 levels is sensitive, and its influence is accompanied by clinical symptoms such as hyper- or hypothyroidism [5,6]. Our results indicate that high T3 concentrations can affect the Hsp90 activity, so decreased Hsp90 activity is expected because ATP remains trapped in the binding pocket. Because of the concentration range and susceptibility, T3 is a smart influencer on Hsp90 activity. Mutations in the ATP-binding site on Hsp90 influence the affinity for geldanamycin; therefore, it is possible that functional conformational changes in HSP90 might be affected by the binding of T3, thereby allosterically affecting the ATP binding site. Consequently, reduced Hsp90 activity is associated with a lower stress-compensation capacity. Unfolded protein aggregates that cannot be removed in time are toxic to cells in the long term [20,21]. On the other hand, the synthesis of T3 itself could also be blocked, because the folding pathways for enzymes that synthesize T3 are disrupted. In addition, the T3 binding site on Hsp90 could also be a target for T3 surrogates or substances, such as those produced by environmental factors that negatively affect protein folding machinery [9].
Open access paper here:
mdpi.com/1422-0067/23/13/71...
A link to brief summaries of several papers about Hsp90:
