A new first responder has its finger on the pulse of evolutionary sensing and disease – Sanjna, Marcus, and Daniel et al’s team work on cardiovascular small heat shock protein just accepted!

Cardiovascular small heat shock protein HSPB7 is a kinetically-privileged reactive electrophilic species (RES) sensor

Invited contribution to the 2018 “Biosensors” Special Issue of ACS Chemical Biology

Sanjna L. Surya#, Marcus J. C. Long#, Daniel A. Urul, Yi Zhao, Emily J. Mercer, Islam M. Elsaid, Todd Evans, and Yimon Aye*

(#, co-first authors. *, corresponding author)

Sanjna is our senior undergraduate researcher and a Biology major entering medical school program the next fall. Daniel is one of our graduate student members and an NSF GRFP fellow. Marcus and Yi are our postdoc colleagues. Islam is one of our sophomore undergraduate researchers and a Chemistry major. Emily and Professor Todd Evans are our collaborators from Weill Cornell Medicine. We thank all of the contributors for this exciting team work!

ABSTRACT

Small heat shock protein (sHSP)-B7 (HSPB7) is a muscle-specific member of the non-ATP-dependent sHSPs. The precise role of HSPB7 is enigmatic. Here we disclose that zebrafish Hspb7 is a kinetically- privileged sensor able to react rapidly with native reactive electrophilic signals (RES), when only sub- stoichiometric amounts of RES are available in proximity to Hspb7 expressed in living cells. Among the two Hspb7-cysteines, this RES-sensing is fulfilled by a single cysteine (C117). Purification and characterizations in vitro reveal that the rate for RES-adduction is among the most efficient reported for protein-cysteines with native carbonyl-based-RES. Covalent-ligand binding is accompanied by structural changes (increase in β-sheet-content) based on circular dichroism analysis. Among the two cysteines, only C117 is conserved across vertebrates; we show that the human ortholog is also capable of RES- sensing in cells. Furthermore, a cancer-relevant missense mutation reduces this RES-sensing property. This evolutionarily-conserved cysteine-biosensor may play a redox-regulatory role in cardioprotection.