Hemeproteins, sensing and hypoxia

During evolution, molecular oxygen has become an essential mediator in the maintenance of cellular structure and function. This has led to the development of several elaborate strategies that tightly regulate oxygen homeostasis in order to allow appropriate cell function and survival. Hem-proteins play an essential role in this process.

Globins are heme-proteins found in all kingdoms of life. Next to the well-known myo- and hemoglobins, several other globin proteins have been discovered including in vertebrates. The great variety of globins has greatly enriched our appreciation of the structural and functional diversity of these proteins and the role they play in sensing and responding to variations in the environment (e.g. drop of oxygen concentration).

That is way we are studying several of these globins in different projects.

Androglobin: a testis specific globin

We identified a new metazoan globin lineage, consisting of large chimeric proteins with an N-terminal protease domain and an internal globin domain named “Androglobins” (Adgb).

  • Expressed in testis with a possible role in fertility
  • Recombinant expression and purification of Adgb and its domains
  • Structural characterization à UV/VIS spectroscopy, EPR, resonance Raman, X-ray crystallography
  • Functional characterization à cellular ROS-experiments, determination of ligand binding kinetics, redox activity and protease activity

Cytoglobin: a tumor supressor

This project focuses on the possible role of cytoglobin as a tumor suppressor.

  • Esophageal, lung and breast cancer: lower expression
  • Hypermethylation of the cytoglobin promotor?
  • Cell culture and epigenetic  studies (QPCR, pyrosequencing)
  • Comparison of orthologs (recombinantly expressed fish and Xenopus cytoglobin)

Neuroglobin and hypoxia

Neuroglobin may play an important role during ischemic stroke and may be considered as a target for the treatment and/or prevention of neuronal ischemic damage after stroke.

  •  Plays a neuroprotective role after hypoxic and ischemic insult
  •  Functions as an oxygen scavenger?
  •  Use of Knock-in (overexpressing) and Knock-out mouse models

C. elegans globins as redox proteins?

In the C. elegans genome, a surprisingly large number of 33 globin genes were found. An increasing number of studies suggest that these globins could play a role in redox signaling and redox biology.

  • Structural and functional characterization of the different globins
  • E.g.  GLB-33: a G-protein coupled receptor with a globin domain

Globin-coupled sensors and biofilms

Globin-coupled sensors are di-domain proteins consisting of a globin domain and a transmitter domain with e.g. an enzymatic function.

  •  Detects fluctuations in environmental gases (e.g. O2 and CO)
  •  Synthesis of c-di-GMP (enzym assay)
  •  Role in biofilm formation
  •  Other virulence factors? (differential proteomics - SILAC)

4D structure of globins

The dynamic motion in globins reacting with ligands needs to be studied as this can lead to essential information on the mechanisms of their function.