Carlos A. Castañeda
Assistant Professor, Biology & Chemistry
Biophysics, biochemistry. Structural biology. Chemical biology. Physical biochemistry. Post-translational modifications. Neurological disorders. Ubiquitin and ubiquitin-like proteins. Nuclear magnetic resonance. Mass spectrometry.
- Postdoctoral Fellow, Biochemistry & Structural Biology, University of Maryland, College Park (2009-2014)
- Ph.D., Biophysics, Johns Hopkins University (2008)
- B.A., Chemistry & Mathematics, La Salle University (2001)
Honors and Awards
- Ralph Powe Junior Faculty Enhancement Award (2016)
- ALS Starter Grant Award (2016)
- Nappi Family Research Award (2016)
- NSF Postdoctoral Fellowship in Biology (2009-2011)
- Burroughs-Wellcome Predoctoral Fellowship (2002-2007)
- BCM 476/676: Biochemistry II (Spring 2015, Spring 2016)
- BCM 678: Perspectives in Biochemistry (Fall 2014, Fall 2015)
- BCM 475: Biochemistry I (Fall 2016)
- CHE 474/674: Structural and Physical Biochemistry (Fall 2016)
Proteins are the biological agents of function in our cells. In humans alone, there are ~20,000 genes coding for different proteins. Each one adopts unique structural and dynamical properties. To add to their complexity, proteins can be covalently modified post-translationally. Some of these modifications are small (deimination/citrullination) while others are large as whole proteins are covalently attached (e.g. ubiquitin and ubiquitin-like proteins). These post-translational modifications (PTMs) can completely alter protein structure and function (e.g. create new protein-protein interactions, elicit new biological signals, unfold the protein). All of these PTMs play significant roles in disease, and in neurodegenerative and neuromuscular disorders including ALS, Alzheimer's and Parkinson's.
Our lab’s goal is to understand the structural, dynamical, and functional consequences of PTMs, as they pertain to neurodegenerative and neuromuscular disorders.
Our lab’s projects center on three areas:
Our lab studies the role of non-canonical ubiquitination in neurological disorders. Ubiquitination, in the form of polyubiquitin chains, can act as signals to activate, degrade, or transport target proteins. The canonical Ub chains (K48 and K63) are involved in protein degradation and DNA repair pathways, respectively. On the other hand, non-canonical Ub chains (chains linked via K6, K11, K27, K29 and K33) are poorly understood. We hypothesize that these linkages are also involved in neurological and neurodegenerative disorders, as they have been implicated in neuronal protection and putatively interact with adaptor proteins that help clear proteins in neurological disorders. Towards this end, we’ve developed chemical biological approaches to assemble these chains (see image on left), and are studying protein-protein interactions involving them.
b) Ubiquitin-like modifications
Recently, a new protein called Ufm1 has been identified and also is covalently attached to target proteins in the form of poly-Ufm1 chains. On a cellular level, it mediates ER stress. Ufm1 and its enzymatic machinery are found in neurons, and dysregulation of Ufm1 pathways are implicated in schizophrenia. Through collaboration with the Broad Institute and others here in the Biology department, we are working to understand the structure, dynamics, and function of this post-translational modification.
c) Shuttle proteins
Shuttle proteins interact with ubiquitin and polyubiquitin chains to bring target proteins to the proteasome or other proteasome-like machinery. We are funded to study one of these shuttle proteins and how it interacts with proteins implicated in ALS (amyotrophic lateral sclerosis). This disease has no known cure; it is a debilitating disease affecting motor neuron function.
Our lab tools:
To tackle our research questions, my lab uses biochemical and biophysical techniques that probe proteins on a molecular level. They include both experimental and computational methods, such as biomolecular nuclear magnetic resonance (NMR), small angle scattering, mass spectrometry, molecular modeling, and dynamics simulations. In addition, we use chemical biology and bio-organic methods to introduce PTMs into target proteins.
Join the lab!
We are always looking for motivated and interested undergraduate and graduate students (both Biology and Chemistry) to further our research program. Visit our webpage to learn more!
1) Ha JH, Karchin JM, Walker-Kopp N, Castañeda CA, Loh SN. (2015) Engineered domain swapping as an on/off switch for protein function. Chem Biol. 10: 1384-93.
2) Castañeda CA, Chaturvedi A, Camara CM, Curtis JE, Krueger S, Fushman D. (2015) Linkage-specific conformational ensembles of non-canonical polyubiquitin chains. Phys Chem Chem Phys DOI: 0.1039/C5CP04601G.
3) Berlin K, Castañeda CA, Schneidman-Duhovny D, Sali A, Nava-Tudela A, Fushman D. (2013) Recovering a representative conformational ensemble from underdetermined macromolecular structural data, J. Am. Chem. Soc. 135: 16595-16609.
4) Castañeda CA, Kashyap TR, Nakasone MA, Krueger S, Fushman D. (2013) Unique structural, dynamical, and functional properties of K11-linked polyubiquitin chains. Structure. 21: 1168-1181.
- Featured in commentary by Cunningham CN, Corn JE. (2013) Decoding a Chain Letter for Degradation. Structure. 21: 1068-1070.
5) Castañeda CA, Dixon E, Kashyap TR, Wang Y, Fushman D. (2013) Nonenzymatic assembly of branched polyubiquitin chains for structural and biochemical studies. Bioorg. Med. Chem. 21: 3421-3429.
6) Castañeda CA, Liu J, Chaturvedi A, Nowicka U, Cropp TA, Fushman D. (2011) Nonenzymatic assembly of natural polyubiquitin chains of any linkage composition and isotopic labeling scheme. J. Am. Chem. Soc. 133: 17855-17868.