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The interior of a cell from a moving protein's point of view

Numerous obstacles posed by cellular structures hinder protein movements within the cell. Heidelberg researchers have succeeded to map the intracellular topology by tracing fluorescently labeled reporter proteins in living cells on multiple time and length scales. By developing a new fluorescence microscopy based technique, Michael Baum and Fabian Erdel from our group succeeded to measure how long it takes proteins to move over distances in the range from 0.2 to 3 µm in living cells. These protein distance versus time maps revealed that the cell's interior appears as a sponge like structure from the point of view of a protein that roams around in the cell. The researchers showed that drugs that target the genome or cytoskeleton have large effects on protein transport in the cell. The results were recently published in the journal Nature Communications.

Cellular structures such as membranes, the cytoskeleton and the DNA genome in the cell nucleus form a dynamic three-dimensional maze through which proteins have to find their way to reach the sites where they are active. Accordingly, the topology of the cellular interior is a key factor for target search processes and enzymatic reactions that are the basis for cell function. While numerous microscopy studies have visualized cellular structures, it is an open question how the internal obstacle network is 'sensed' in living cells by a diffusing protein. To address this issue, we devised a method to infer the cellular topology from the random motion of proteins. "Proteins moving within the cell, that's much like the game marble maze", says Michael Baum, first author of the study who conducted the work as part of his PhD thesis at the University of Heidelberg. "It is easy for marbles to move for small distances but then they collide with a wall and are slowed down as they move along."

Protein mobility in the cell can be compared to a marble in a labyrinth game: On short distances the marble moves fast until it hits an obstacle. This results in a 'stop-and-go' like path with a slowed down average speed to move over larger distances. By including the average distance between obstacles as a third parameter the researchers found a mathematical model that described the measured mobility of proteins in the cell.

By analyzing the relation between protein translocations and time the Heidelberg researchers were able to reconstruct the intracellular topology with a resolution significantly below that of a light microscopy image. They found that a model of a porous medium like it is found in a sponge described the obstacle structure encountered by a protein that moves through the cell. In this dynamic structure larger proteins became occasionally trapped for several minutes. Furthermore, drugs used in cancer chemotherapy or treatment of malaria that change the organization of the genome were found to also affect the mobility of proteins in the nucleus. We now plan to apply our new approach to further study the interplay between drug-induced changes of cellular structure and protein transport as well as the disease-related deregulation of this process.

The project was supported by the German Federal Ministry of Education and Research (BMBF) within the SysTec and e:Bio programs.

Baum, M., Erdel, F. Wachsmuth, M. & Rippe, K. (2014). Retrieving the intracellular topology from multi-scale protein mobility mapping in living cells. Nat. Commun. 5, 4494. doi: 10.1038/ncomms5494 | Abstract | Reprint (6.4 MB)

Read the English press release or the German press release press release from the University of Heidelberg

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