Minireview HMGA molecular network: From transcriptional regulation to chromatin remodeling Riccardo Sgarra, Salvina Zammitti, Alessandra Lo Sardo, Elisa Maurizio, Laura Arnoldo, Silvia Pegoraro, Vincenzo Giancotti, Guidalberto Manfioletti ⁎ Department of Life Sciences, University of Trieste, via L. Giorgieri, 1-34127 Trieste, Italy abstract article info Article history: Received 21 August 2009 Accepted 24 August 2009 Available online 2 September 2009 Keywords: Intrinsically disordered proteins Protein–protein interaction Architectural transcription factors Cancer Nuclear functions rely on the activity of a plethora of factors which mostly work in highly coordinated molecular networks. The HMGA proteins are chromatin architectural factors which constitute critical hubs in these networks. HMGA are referred to as oncofetal proteins since they are highly expressed and play essential functions both during embryonic development and neoplastic transformation. A particular feature of HMGA is their intrinsically disordered status, which confers on them an unusual plasticity in contacting molecular partners. Indeed these proteins are able to bind to DNA at the level of AT-rich DNA stretches and to interact with several nuclear factors. In the post-genomic era, and with the advent of proteomic tools for the identification of protein–protein interactions, the number of HMGA molecular partners has increased rapidly. This has led to the extension of our knowledge of the functional involvement of HMGA from the transcriptional regulation field to RNA processing, DNA repair, and chromatin remodeling and dynamics. This review focuses mainly on the protein–protein interaction network of HMGA and its functional outcome. HMGA molecular partners have been functionally classified and all the information collected in a freely available database (http://www.bbcm.units.it/∼manfiol/INDEX.HTM). © 2009 Elsevier B.V. All rights reserved. 1. HMGA proteins: multifunctionality through adaptability For more than 75 years it has been believed that the specific functionality of a given protein is predetermined by its unique 3-D structure. For these structured proteins, the sequence →structure → function paradigm has become paramount. Evidence is rapidly accumulating that many protein regions and even entire proteins lack stable tertiary and/or secondary structure in solution, yet possess crucial biological functions [1]. These regions have a high content of amino acid residues that are known to promote disorder and to be enriched in “intrinsically disordered“ (ID) proteins. The number of identified ID proteins is growing rapidly and it is estimated that about 1/3 of all eukaryotic proteins contain at least one extended amino acid stretch in an unfolded state [2]. An unfolded state implies a conformational flexibility that allows ID proteins to overcome steric restrictions and, in this way, to adapt to several different protein surfaces [2]. ID proteins undergo disordered-to-ordered transition upon binding to their molecular partners and this structural change is necessary for ID proteins to manifest their functions. These proteins are mainly involved in cell signaling pathways and this implies that their functions must also be highly and finely modulated [3]. This fits perfectly with the observation that ID proteins can contact several different partners with high specificity but low affinity [2], that is to say that highly specific interactions can be perturbed by simple and rapid mechanisms involving, for instance, post-translational modifications. HMGA proteins are considered prototypes of this particular protein family [1,4]. These proteins have a high content of K, R, E, D, and P amino acid residues, which are clustered at the level of their DNA binding domains (R, K, and P) and of their acidic C-terminal tail (E and D) [5]; all these residues are typical of ID proteins. HMGA is a group of proteins formed by HMGA1a and HMGA1b, which are alternatively spliced products of the same gene HMGA1 (formerly (HMGI/Y), and HMGA2 (formerly HMGI-C) which is the product of a different but related gene [5]. These proteins are involved in several different biological processes, ranging from embryonic development, cell differentiation and transformation, cell cycle progression, apopto- sis, senescence, up to different aspects of cell physiopathology [5–7]. As will emerge from this review, HMGA proteins are highly connected hubs in the chromatin network, establishing a huge number of protein–protein interactions and, at the same time, it is striking that these proteins can be widely post-translationally modified by several different kinases, acetyl- and methyl-transferases, and by other modifying enzymes [8]. Regarding this aspect, it is noteworthy to mention that HMGA proteins have been proposed to function as “molecular switches” in the context of macromolecular transcriptional complex assembly [9]. In this light, both the intrinsically disordered status and the pattern of post-translational modifications of HMGA proteins could be the key to explaining their multifunctionality through adaptability. A model of the interplay between ID status and post-translational Biochimica et Biophysica Acta 1799 (2010) 37–47 ⁎ Corresponding author. Tel.: +39 040 5583675; fax: +39 040 5583694. E-mail address: manfiole@units.it (G. Manfioletti). 1874-9399/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagrm.2009.08.009 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm