Christian Kaiser joined the Department of Biology in 2013 as assistant professor. He holds a joint appointment in the Department of Biophysics, as well as in the Johns Hopkins University School of Medicine Department of Biophysics and Biophysical Chemistry. Prior to coming to Hopkins, he did postdoctoral work at the University of Texas Medical Branch at Galveston, and the University of California, Berkeley.
How proteins fold into their functional native structures remains a central question in biology, particularly for multi-domain proteins that make up a large fraction of all proteomes. We want to understand how cellular machineries, in particular ribosomes and molecular chaperones, contribute to efficient folding in the cell. The ultimate goal is to determine the mechanisms that govern protein synthesis and folding, and to understand how these processes are orchestrated in the cell. This knowledge may help us to design and produce novel proteins, and to understand the mechanisms underlying protein misfolding, which is observed in a number of diseases.
Folding of multi-domain proteins begins co-translationally, while the ribosome still elongates the nascent polypeptide chain. As a consequence, these proteins acquire stable structure during synthesis. Domain-wise folding during protein synthesis represents a conceptually straightforward way of simplifying the conformational search for the native state. Our recent work has shown that (1) interactions with the ribosome itself and with molecular chaperones modulate the folding of nascent proteins, (2) folding is complicated in unanticipated ways by interactions among native and non-native domains in emerging proteins, and (3) nascent chain-binding chaperones fulfill previously unrecognized functions to help folding.
We are using single-molecule biophysical approaches to map the folding energy landscapes of nascent proteins. Mechanical manipulation of individual protein molecules with optical tweezers is a powerful approach for following folding directly, yielding folding rates and one-dimensional structural information. This single-molecule technique is ideally suited for studies of complex proteins and circumvents the complication of protein aggregation. Applying this technique to nascent proteins emerging from the ribosome, we are defining their folding pathways and interactions with molecular chaperones. We are also developing approaches to define folding waypoints in live cells to complement our single-molecule in vitro experiments. Collectively, these studies contribute unique but complementary mechanistic insights to our overall understanding of protein folding in a cellular context and may help to develop therapeutic interventions for protein misfolding diseases.
Liu, K., Maciuba, K. and Kaiser C.M. (2019) The ribosome cooperates with a chaperone to guide multi-domain folding. Mol Cell (in press)
Kaiser, C.M. and Liu, K. (2018) Folding up and moving on – Nascent protein folding on the ribosome. J Mol Biol 430:4580-4591
Liu, K., Rehfus, J., Mattson, E. and Kaiser C.M. (2017) The ribosome destabilizes native and non-native structures in a nascent multidomain protein. Protein Sci 26:1439-1451
Motlagh, H.N., Toptygin, D., Kaiser, C.M. & Hilser, V.J. (2016) Two-dimensional single-molecule force-spectroscopy provides structural access to protein folding. Biophys J 110:1280-90
Goldman, D.H.*, Kaiser, C.M.*#, Milin, A., Righini, M., Tinoco Jr., I., and C. Bustamante. (2015) Mechanical force releases nascent chain-mediated ribosome arrest in vitro and in vivo. Science 348: 457-60. *equal contributions #corresponding authors
Bustamante, C., Kaiser, C.M., Maillard, A.R., Goldman, D. and C. Wilson. (2014) Mechanisms of cellular proteostasis: Insights from single molecule approaches. Annu Rev Biophys 43, 119-40.
Kaiser, C.M., P. Bujalowski, L. Ma, J. Anderson, H.F. Epstein, and A.F. Oberhauser. (2012) Tracking UNC-45 chaperone-myosin interaction with a titin mechanical reporter. Biophys. J. 102:2212-2219.
Kaiser, C.M., D. Goldman, J. Chodera, I. Tinoco, and C. Bustamante. (2011) The ribosome modulates nascent protein folding. Science 344:1723-1727. Maillard, A.R., G. Chistol, M. Sen, M. Righini, J. Tan, C.M. Kaiser, C. Hodges, A. Martin, and C. Bustamante. (2011) ClpX generates mechanical force to unfold and translocate its protein substrates. Cell 145:459-469.
Lakshmipathy, S. K., Tomic, S., Kaiser, C. M., Chang, H. C., Genevaux, P., Georgopoulos, C., Barral, J. M., Johnson, A. E., Hartl, F. U. and S.A. Etchells. (2007) Identification of nascent chain interaction sites on trigger factor. J Biol Chem 282, 12186-93.
Kaiser C.M., Chang H.C., Agashe V.R., Lakshmipathy S.K., Etchells S.A., Hayer-Hartl M., Hartl F.U. and Barral J.M. (2006) Real-time observation of trigger factor function on translating ribosomes. Nature 444:455-60
Pew Scholar, Class of 2015