Intrinsically disordered features of carbonic anhydrase IX proteoglycan-like domain
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Cellular and Molecular Life Sciences
REVIEW
Intrinsically disordered features of carbonic anhydrase IX proteoglycan‑like domain Emma Langella1 · Martina Buonanno1 · Giuseppina De Simone1 · Simona Maria Monti1 Received: 28 July 2020 / Revised: 26 September 2020 / Accepted: 31 October 2020 © Springer Nature Switzerland AG 2020
Abstract hCA IX is a multi-domain protein belonging to the family of hCAs which are ubiquitous zinc enzymes that catalyze the reversible hydration of CO2 to HCO3− and H +. hCA IX is a tumor-associated enzyme with a limited distribution in normal tissues, but over-expressed in many tumors, and is a promising drug target. Although many studies concerning the CA IX catalytic domain were performed, little is known about the proteoglycan-like (PG-like) domain of hCA IX which has been poorly investigated so far. Here we attempt to fill this gap by providing an overview on the functional, structural and therapeutic studies of the PG-like domain of hCA IX which represents a unique feature within the CA family. The main studies and recent advances concerning PG role in modulating hCA IX catalytic activity as well as in tumor spreading and migration are here reported. Special attention has been paid to the newly discovered disordered features of the PG domain which open new perspectives about its molecular mechanisms of action under physiological and pathological conditions, since disorder is likely involved in mediating interactions with partner proteins. The emerged disordered features of PG domain will be explored for putative diagnostic and therapeutic applications involving CA IX targeting in tumors. Keywords IDPs · IDRs · Hypoxic tumour · Disease · Disorder · Natively unfolded · Carbonic anhydrase
Introduction Proteins play fundamental roles in living cells. Despite the dogma that the three-dimensional structure of a protein confers its biological functionality, it is now assessed that proteins or regions of them may lack stable secondary and/or tertiary structures in solution and still fulfill key biological functions [1–3]. These proteins or protein regions, hereafter referred as intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs), are widely distributed in nature [4–7] and are more abundant in eukaryotes compared to archaea and bacteria [4, 8–10]. Indeed, among eukaryotes about 25–30% of proteins are mostly disordered [4, 6], and more than half possesses extended regions of disorder [4, 8, 9].
* Emma Langella [email protected] * Simona Maria Monti [email protected] 1
Institute of Biostructures and Bioimaging, CNR, via Mezzocannone, 16, 80134 Naples, Italy
In humans, IDPs/IDRs are often associated to diseases such as amyloidosis, cardiovascular diseases, neurodegenerative diseases, diabetes, and cancer where the disorder is used to mediate and modulate interactions with other proteins or nucleic acids [11]. The abundance of intrinsic disorder in proteins involved in various pathological conditions highlights the importance of this feature
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