Stefan Arold

  Associate Professor, Bioscience ​

  Office Location: Ibn Al Haytham (Building 2) · Level 4 · Room 4275
  Email: stefan.arold@kaust.edu.sa


Research Keywords
Integrated structural biology; biophysical assays; protein engineering; bioinformatics; x-ray crystallography; small angle x-ray scattering; molecular basis for cellular signaling; multidomain proteins.


Research Interests
Research in Prof. Arold's group is dedicated to elucidating the molecular basis of the function and (de)regulation of proteins central to cellular signalling networks. The specificity, adaptability and robustness of signalling networks arises from multiple transient interactions among multidomain proteins, often embedded within ‘signalosomes’. The intermediate size and dynamic nature of the proteins involved often precludes conventional three-dimensional (3D) structural analysis. Our investigations are therefore based on an integrated structural biology approach that combines functional and structural data from multiple sources (see ‘Main Techniques’ below). Using these approaches we investigate in particular kinase-mediated signalling networks. 

One major focus of my group is on the structure and function of Focal adhesion (FA)–associated proteins. FAs are large macromolecular assemblies through which the actin cytoskeleton is connected to the extracellular matrix (ECM). More than just anchoring the cell, FAs encode the state of the ECM into intracellular biochemical pathways that control cell morphology, migration, differentiation, proliferation, and survival. We have recently determined the molecular basis for site-specific activation of full-length FA kinase (FAK) (Brami-Cherrier, 2014; see Figure). We now use this 3D molecular framework of FAK to understand how the close FAK homologue Pyk2 has evolved the unique capacity of calcium-sensing. Both FAK and Pyk2 have elicited great interest because of their important roles in human health (including cancer invasiveness, heart dysfunction and neurodegeneration). We will therefore also pursue opportunities for medical intervention against erroneous activation of these molecules through targeted intramolecular or intermolecular interaction inhibitors. 

In addition, we combine experimental and in silico structural biology methods with computer science and (high-throughput) biophysical assays to functionally annotate local microbes. In collaboration with Uli Stingl (RSRC, KAUST), we have assigned function to all hypothetical proteins of the SAR11 lineage of bacteria. Experimental assays will be used to confirm in silico results to understand how SAR11 has managed to become the most ubiquitous organism in the oceans, and how SAR11 has adapted to the harsh conditions of the Red Sea. In parallel, embedded in the CBRC flagship project, we will use similar approaches to understand and engineer key proteins of selected local microbes, in view of developing microbial cell factories. Other protein engineering projects aim at using DNA-protein conjugates or engineered multidomain proteins to produce novel biomolecules with beneficial properties (enzymes, switches, genetic/epi-genetic regulators, detectors).

 
 

Main Techniques
We combine experimental structural biology methods (mainly X-ray crystallography, small angle X-ray scattering and nuclear magnetic resonance), bioinformatics & computer sciences (homology modeling, machine learning algorithms), genetic engineering, biochemistry and high-throughput or high-precision biophysical assays (flurescence spectroscopy, microcalorimetry, microscale thermophoresis, dynamic light scattering, analytical ultracentrifugation and others). Results obtained are correlated with cell biology, through close collaborations.

Members of the Lab

Dr. Abdirahman M. Jama: Post-doctoral fellow dissecting how Ca2+/calmodulin regulates focal adhesion proteins, and promotes aggressive invasiveness in some cancer types. Understanding the atomic mechanism of calmodulin-dependent calcium sensing might usher in novel small molecule therapeutic drugs. This research is carried out using biophysical/biochemical techniques that include X-ray crystallography, small angle X-ray scattering, spectrofluorimetry and isothermal titration. Although Dr. Abdirahman obtained his PhD from Edinburgh University, (United Kingdom), nobody has seen him in a kilt yet.

Dr. Katarzyna W. Walkiewicz: Post-doctoral fellow focusing on characterisation and understanding of protein-protein interactions using combinatorial structural and biophysical/biochemical approaches including x-ray crystallography, isothermal titration calorimetry, florescence spectroscopy and thermophoresis. Dr. Walkiewicz obtained her PhD from Rice University (USA) and can explain the five different versions of the sound ‘wsh’ used in Polish language.

Dr. Umar Shahul Hameed: Post Doctoral Fellow focusing on characterising proteins structure and function using X-ray crystallography and biophysical techniques and applying them to answer key biological questions. He is particularly interested in characterizing MAP kinase family proteins, which are responsible for plant immunity and resistance to stressed conditions. Dr. Hameed obtained his PhD from National University of Singapore, and gets regular advice for his lab work from his 6-year old daughter.

Mr. Afaque Momin: Second-year PhD student studying the structural and functional basis of focal adhesion proteins to understand their role in promoting cancer cell invasiveness. His research combines computational methods (molecular dynamics and bioinformatics) with experimental methods (biophysics and structural biology). He received his Master of Science (Bioinformatics) from the University of Mumbai, Mumbai (India), and will bring you India’s best mangoes when you expect it least.

Ms. Rayan Naser: Second-year PhD student, studying structure and function of key complexes involved in focal adhesion assembly and control. She uses a combination of biophysical assays in addition to computational and cell biology methods. Ms Naser obtained her Master degree from the American University of Beirut (Lebanon), and she is the one to ask for the second best Lebanese bakery (after her mother).

Ms. Safia Aljedani:  Second-year PhD student studying the structure and function of ligand-based activation of the phosphoinositide 3 kinase (PI3K). To study multi-domain protein-protein complexes she uses a combination of biophysical, computational and cell biology methods. She received her MSc from KAUST, and can tell a camel spider from a tarantula.

Mr. Abdullah Al-Amoudi: A masters student who joined the group in spring 2015. He is constructing a FRET sensor to screen focal adhesion proteins for inhibitors as potential cancer drugs. He got his MBBS from King Abdulaziz University in Jeddah (KSA) and is now making the attempt for healing through science.

Ms. Regina Baur: joined our group with a VSRP, which probably means ‘visiting student research programme’. She is investigating the structure-function relationship of MAP kinases, and knows about the only French territory located in Bavaria. She has received her MSc (Biochemistry) from the Technische Universität in Munich (Bavaria)

Mr. Arnaud Hungler: Computer scientist whose main goal is the establishment of a truly integrated functional annotation pipeline for protein sequences. Interestingly, this task includes writing code that emulates the group leader, Prof Arold. Needless to say that Prof Arold is eager to see that programme (do his) work. Mr. Hungler graduated from the École des Mines de St-Étienne (France).

Ms. Franceline Huser:  Lab Manager involved in general lab management, while working on biochemistry and structural analysis of proteins. In addition to assisting researchers in the lab with their experiments, she pursues her own research projects based on understanding the impact of the dark side of penguins on climate change. Ms Huser received an MSc in Medical Biology from the University of Lausanne (Switzerland).

Ms. Hyeryeung Noh: Lab technician working on the lab management and technical assistance to support researchers in the lab. She received her MS in Chemical Engineering from the Chungbunk National University (S. Korea). She is the second most knowledgeable person in the lab for greetings in different languages.

Ms. Thasneem F. Kamarudeen: Admin Assistant working on the lab management and a myriad of other admin jobs required for smooth operations. She received her Bachelors in Economics from the Ethiraj College for Women, Chennai (India).    


Selected Publications
Cheung WT, Walkiewicz KW, Besong TMD, Guo H, Hawke DH, Arold ST*, Mills GB*. (2015) Regulation of the PI3K Pathway through a p85a Monomer-Homodimer Equilibrium. eLIFE, 4, doi: 10.7554/eLife.06866​

Brami-Cherrier K, Gervasi N., Arsenieva D, Walkiewicz K., Boutterin MC, Ortega A, Leonard PG, Seantier B, Gasmi L, Bouceba T, Girault JA, Arold ST. (2014) FAK dimerization controls its kinase-dependent functions at focal adhesions. EMBO J. 3,356-370.

Suen KM, Lin CC, George R, Melo FA, Biggs, ER, Ahmed Z, Drake MN, Arur S, Arold ST, Ladbury JE (2013) Interaction with Shc prevents aberrant Erk activation in the absence of extracellular stimuli. Nat. Struct. Mol Biol. 20, 620-7

Lin CC, Melo FA, Ghosh R., Suen KM, Stagg LJ, Kirkpatrick J., Arold ST., Ahmed A., Ladbury JE (2012) Inhibition of basal FGF receptor signaling by Grb2. Cell, 149, 1514-24

Arold ST (2011) How focal adhesion kinase achieves regulation by linking ligand binding, localization and action. Curr Opin Struct Biol. 21, 808-13